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1
Chiara, S., S. Lastraioli, P. Marroni, L. Gargiulo, F. Leonardi, A. Ponzanelli, E. Franzini, L. Boni, M. Paganuzzi, and R. Notaro. "Polymorphisms in UGT1A gene family and irinotecan toxicity in patients with advanced colorectal cancer." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13049. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13049.
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13049 Background: The irinotecan active metabolite, SN38, is inactivated through glucuronidation mainly by uridine diphosphate glucuronosyltransferase (UGT) 1A1. The (TA)7 allele of a polymorphism in UGT1A1 promoter has been associated with reduced SN38-glucuronidation rate and more severe toxicity. Since other UGT1A family isoforms, the extrahepatic UGT1A7 and the hepatic UGT1A9, are involved in SN38 glucuronidation, it has been suggested that also polymorphic variants of these genes may affect irinotecan toxicity. Methods: 84 patients with advanced colorectal cancer received an irinotecan-based (180 mg/m2 q.2wks) combination treatment. Polymorphisms of UGT1A1 [(TA)6>7], UGT1A7 [387T > G, 391–2CG > AA, 622T > C] and UGT1A9 [-118(T)9>10, -87G > A, 98T > C, I152G > A] were identified by sequencing on DNA from blood samples obtained under an IRB approved protocol. Toxicity has been graded according to NCI-CT criteria. Results: Patient median age was 64 y (range: 31–82); median PS was 0 (range: 0–2). Severe toxicity (diarrhea or/and neutropenia ≥G3) has been observed in 32 patients: diarrhea in 11, neutropenia in 25 (4 patients had both). The estimated allele frequencies were as follows: UGT1A1, (TA)7 (0.35); UGT1A7, 387T and the completely linked 391–2CG (0.39), 622C (0.39); UGT1A9, -118(T)10 (0.39), -87A (0.05), T98C (0.02), I152A (0.21). Severe toxicity was significantly associated only with: (a) the UGT1A1 (TA)7 allele [severe toxicity in 25% of (TA) 6/6, in 46% of (TA) 6/7, in 55% of (TA) 7/7 (Mantel-Haenszel trend test, P < 0.03)]; and (b) the low activity UGT1A7 622C allele [severe toxicity in 26% of 622 T/T, in 39% of 622 T/C, in 67% of 622 C/C (Mantel-Haenszel, P < 0.02)]. In addition, the analysis of the combined genotypes [(TA)6>7 and 622T > C] has shown severe toxicity in 21% of patients with none of (TA)7 and of 622C alleles, in 43% of patients in which the sum of the number of (TA)7 and of 622C alleles is 1 or 2, in 57% of patients in which this sum is ≥3 (the latter includes all patients with both toxicities) (Mantel-Haenszel, P < 0.02). Conclusions: These data show that both the low activity UGT1A1 (TA)7 and UGT1A7 622C alleles are significantly associated with irinotecan severe toxicity. It is to evaluate if their combined genotype may be a better predictor of toxicity. No significant financial relationships to disclose.
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Romero, D., G. Romero, G. Veneranda, L. Filippi, D. Racca, and G. A. Bó. "18 PREGNANCY RATES IN LACTATING DAIRY COWS TREATED WITH GONADOTROPIN-RELEASING HORMONE-BASED SYNCHRONIZATION PROGRAMS AND INSEMINATED AT A FIXED TIME." Reproduction, Fertility and Development 25, no. 1 (2013): 156. http://dx.doi.org/10.1071/rdv25n1ab18.
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An experiment was designed to compare pregnancy rates in lactating dairy cows synchronized with a 7-day CIDR-Synch or a 5-day CIDR-Synch program and to determine if the addition of a second prostaglandin F2α (PGF) injection to the 7-day CIDR-Synch program would improve pregnancy rates following fixed-time AI (FTAI). The experiments were performed on 2 dairy farms in Argentina, with year-round calving and a mixed feeding system (35% grazing plus 65% corn silage and grain). Cows (n = 621) were 39.3 ± 6.5 days in milk (DIM, mean ± SD) when they were enrolled in the program, had 2.4 ± 1.5 lactations and a body condition score (BCS) of 3.1 ± 0.2 (range: 2.7 to 4.0). All cows received a pre-synchronization treatment with 2 doses of prostaglandin (PGF, 25 mg of dinoprost, Lutalyse, Pfizer Animal Health, Argentina) 14 days apart, and 11 days after the second PGF (Day 0) received 10 µg of Buserelin (GnRH, Receptal, MSD-Intervet, Argentina) and a CIDR device (1.9 g of progesterone, Pfizer Animal Health). Cows were randomly allocated to 1 of 3 groups. The CIDR devices were removed and PGF was administered to cows in Groups 1 and 2 on Day 7. A second GnRH was given 56 h later and cows experienced FTAI 16 h after gonadotropin-releasing hormone (GnRH) injection (i.e. 72 h after CIDR removal). Cows in Group 2 also received a second PGF injection on the afternoon of Day 7. Cows in Group 3 had the CIDR removed and received 2 PGF injections 12 h apart on Day 5. A second dose of GnRH was given and FTAI was performed at the same time, on Day 8 (i.e. 72 h after CIDR removal). All cows were examined by ultrasonography (Aloka 500V, Aloka, Tokyo, Japan) on the day of the first PGF injection and at CIDR removal to determine the presence and number of corpora lutea (CL), and 30 days after FTAI to determine pregnancy status. Data were analyzed by logistic regression to determine the effects of treatment, parity, days postpartum, milk production, BCS, presence of a CL at enrollment, and number of CL at the time of CIDR removal on pregnancy rates. Overall pregnancy rates did not differ among groups: 32.9% (68/207), 38.2% (78/204), and 38.3% (80/209) for Groups 1, 2, and 3, respectively (P = 0.2). Although the number of CL present at CIDR removal did not significantly affect pregnancy rates (P = 0.4), pregnancy rates in cows with 1 CL in Groups 1 and 2 tended to differ [29.0% (11/38) v. 48.9% (21/43); P < 0.07], but neither differed from that in Group 3 [37.2% (16/43)]. No differences were detected among groups in cows without a CL at CIDR removal [overall pregnancy rate: 29.4% (5/17)] and those with ≥2 CL [overall pregnancy rate: 36.1% (173/479)]. Among the other variables evaluated, first-parity cows had 1.96 (1.38–2.78) times more chance of getting pregnant than second-or-more-parity cows (P = 0.002) and cows with BCS >3 had 1.63 (1.16–2.28) times more chance of getting pregnant than those with BCS <3 (P = 0.003). Finally, herd, days postpartum, milk production, and presence of a CL at enrollment did not significantly affect pregnancy rates. We concluded that the 3 treatments resulted in similar pregnancy rates for lactating dairy cows and that the benefit of adding a second PGF injection to the 7-day protocol was only marginal in cows with 1 CL at CIDR removal.
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Oto, Hanuš, Křížová Ludmila, Hajšlová Jana, Lojza Jaromír, Klimešová Marcela, Janů Libor, Roubal Petr, Kopecký Jaroslav, and Jedelská Radoslava. "Effect of increasing zearalenone levels on the coagulation properties of milk and the viability of yogurt bacteria." Czech Journal of Food Sciences 36, No. 4 (September 3, 2018): 277–83. http://dx.doi.org/10.17221/391/2017-cjfs.
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The effect of increasing levels of zearalenone (ZEA) artificially supplemented to milk on the coagulation characteristics and the viability of Lactobacillus bulgaricus and Streptococcus thermophilus was examinated. Cow milk was inoculated with the yogurt culture YC-180 – YO-Flex and divided into 72, 25-ml flasks. Two samples were collected before fermentation (0 h) and remaining 70 flasks were divided into 7 groups – control (C), Z0 with 0.5 ml of ethanol and Z10, Z100, Z250, Z500, and Z1000 that were spiked with ZEA to reach the final ZEA concentrations of 10, 100, 250, 500, and 1000 µg/l, respectively. Samples were fermented at 43 ± 2°C for 5 hours. Two samples per group were collected at 1-h intervals and analysed on pH, titratable acidity, ZEA and count of Lb. bulgaricus and Str. thermophilus. The addition of ZEA resulted in slower acidification in Z100, Z250, Z500, and Z1000. The highest ZEA binding capacity (25%) was observed in Z10 and the lowest (3.1%) was found in Z1000.
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Huang, Tao, Terri Beaty, Ji Li, Huijuan Liu, Wei Zhao, and Youfa Wang. "Association between dietary fat intake and insulin resistance in Chinese child twins." British Journal of Nutrition 117, no. 2 (January 25, 2017): 230–36. http://dx.doi.org/10.1017/s0007114516004542.
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AbstractDietary fat intake is correlated with increased insulin resistance (IR). However, it is unknown whether gene–diet interaction modulates the association. This study estimated heritability of IR measures and the related genetic correlations with fat intake, and tested whether dietary fat intake modifies the genetic influence on type 2 diabetes (T2D)-related traits in Chinese child twins. We included 622 twins aged 7–15 years (n 311 pairs, 162 monozygotic (MZ), 149 dizygotic (DZ)) from south-eastern China. Dietary factors were measured using FFQ. Structural equation models were fit using Mx statistical package. The intra-class correlation coefficients for all traits related to T2D were higher for MZ twins than for DZ twins. Dietary fat and fasting serum insulin (additive genetic correlation (rA) 0·20; 95 % CI 0·08, 0·43), glucose (rA 0·12; 95 % CI 0·01, 0·40), homoeostasis model of assessment-insulin resistance (Homa-IR) (rA 0·22; 95 % CI 0·10, 0·50) and the quantitative insulin sensitivity check index (Quicki) (rA −0·22; 95 % CI −0·40, 0·04) showed strong genetic correlations. Heritabilities of dietary fat intake, fasting glucose and insulin were estimated to be 52, 70 and 70 %, respectively. More than 70 % of the phenotypic correlations between dietary fat and insulin, glucose, Homa-IR and the Quicki index appeared to be mediated by shared genetic influence. Dietary fat significantly modified additive genetic effects on these quantitative traits associated with T2D. Analysis of Chinese twins yielded high estimates of heritability of dietary fat intake and IR. Genetic factors appear to contribute to a high proportion of the variance for both insulin sensitivity and IR. Dietary fat intake modifies the genetic influence on blood levels of insulin and glucose, Homa-IR and the Quicki index.
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Johnson, Bruce E., Mark G. Kris, Lynne D. Berry, David J. Kwiatkowski, Anthony John Iafrate, Marileila Varella-Garcia, Ignacio Ivan Wistuba, et al. "A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8019. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8019.
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8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (<1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p<0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.
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Alluaibi, Abutalib B., Bahaa K. Hassan, Alaa H. Ali, and Ahmed A. Muhsen. "Determinants of conversion during laparoscopic cholecystectomy among a sample of Iraqi patients." International Surgery Journal 5, no. 7 (June 25, 2018): 2455. http://dx.doi.org/10.18203/2349-2902.isj20182462.
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Background: Laparoscopic cholecystectomy has become a standard technique for gall bladder surgery of symptomatic cholelithiasis. However, conversion to open cholecystectomy is sometimes necessary. The aim of the present study was to assess the predictive factors that increase the possibility of conversion of laparoscopic cholecystectomy to open cholecystectomy.Methods: A total of 621 laparoscopic cholecystectomies were attempted at AL-Mawanee General Hospital and AL-Sader Teaching Hospital in Basrah, IRAQ from June 2012 till June 2016.Of these,43 had to be converted to open cholecystectomies. Patients assessed according to different factors, including age, sex, acute cholecystitis, adhesions of gallbladder and calot's triangle, obesity, previous abdominal surgery, anatomical variation of gallbladder and Calot's triangle and intraoperative complications (bleeding, bile duct injury, visceral injury).Results: Conversion to open cholecystectomy was performed in 43 patients (6.92%). The significant factors for conversions were adhesions of gallbladder and Calot's triangle(39.53%) followed by acute cholecystitis(34.88%). Rate of conversion in other factors are as the following i.e., isolated male gender (0%), age (0%), previous abdominal surgery (9.3%), obesity (2.33%), anatomical variations of gall bladder and calot's triangle (2.33%), intra operative complications including bleeding (4.65%), bile duct injury (4.65%), visceral injury (2.33%) were insignificant factors for conversion.Conclusions: Adhesions of gallbladder and calot's triangle is the most common predictive factor and cause for conversion from laparoscopic cholecystectomy to open cholecystectomy. Acute cholecystitis found to be the strongest factor for conversion despite its incidence is lower than adhesions of gall bladder and calots triangle. Male gender and age more than fifty years are not direct predictive factors for conversions.
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Foeldvari, I., J. Klotsche, O. Kasapcopur, A. Adrovic, K. Torok, M. T. Terreri, A. P. Sakamoto, et al. "POS0079 PATIENTS WITH JUVENILE SYSTEMIC SCLEROSIS HAVE A DISTINCT PATTERN OF ORGAN INVOLVEMENT.RESULTS FROM THE JUVENILE SYSTEMIC SCLEROSIS INCEPTION COHORT. WWW.JUVENILE-SCLERODERMA.COM." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 247.2–247. http://dx.doi.org/10.1136/annrheumdis-2021-eular.799.
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Background:Juvenile systemic sclerosis (jSSc) is a rare disease with a prevalence of around 3 in 1,000,000 children. To better capture the clinical manifestations of jSSc the juvenile systemic sclerosis inception cohort (jSScC) has been prospectively enrolling patients with predetermined clinical variables over the past 12 years. One of the goals is to study the demographic, clinical features, and physician and patient reported outcome differences between those with juvenile limited cutaneous (lc) compared to diffuse cutaneous (dc) disease subtypes, to determine if characteristics are similar or different between dc and lc jSSc.Objectives:Evaluation of the baseline clinical characteristics of jSSc patients in the jSScC. Compare clinical phenotype between diffuse (dcjSSc) and limited cutaneous (lcjSSc) subtypes.Methods:Demographic, physical examination, organ system evaluation, autoantibody profile, treatment, and patient and physician reported outcome variables were evaluated from the jSSc Inception cohort and summary statistics applied using chi-square test and Mann Whitney U-test comparing lcjSSc and dcjSSc subtypes.Results:At the time of data extraction, 175 jSSc patients were enrolled in the cohort, 81% were Caucasian and 81% female. Diffuse cutaneous jSSc subtype predominated (73%). Mean disease duration was 3.1 year (±2.7). Mean age at Raynaud´s was 10 years (+3.8) and mean age of first non-Raynaud´s was 10.2 years (±3.8). Significant differences were found between dcjSSc versus lcjSSc, regarding several clinical characteristics. Patients with diffuse cutaneous subtype had significantly higher modified Rodnan skin score (p=0.001), presence of sclerodactyly (p=0.02), presence of Gottron’s papules (p=0.003), presence of telangiectasia (p=0.001), history of digital tip ulceration (p=0.01), and frequency of elevated CK value (p=0.04). Cardiac involvement was significantly higher in limited cutaneous jSSc subtype (p=0.02). Diffuse cutaneous jSSc patients had significantly worse scores for Physician Global Assessment of disease activity (38 vs 25; p=0.002) and disease damage (34 vs 19; p=0.008).Table 1.Comparison of demographic data and significant differences between dcjSSc and lcjSSc at time of inclusionWhole CohortN=175Diffuse SubtypeN=128Limited SubtypeN=47P valueFemale to Male Ratio4.3:1 (142/33)4.1:1 (103/25)4.8:1 (39/8)0.829Cutaneous subtypeDiffuse subtype73% (128)1280Limited subtype27% (47)047Mean Disease duration (years)3.1 (± 2.7)3.3 (± 2.9)2.6 (± 2.2)0.135Mean age of onset of Raynaud´s (years)10.0 (± 3.8)17 non-Raynaud9.8 (± 3.6)10 non-Raynaud10.6 (± 4.3)7 non-Raynaud0.219Mean age of onset of non-Raynaud´s (years)10.2 (± 3.9)10.0 (± 3.7)10.9 (± 4.3)0.173Disease modifying drugs88% (154)89% (114)85% (40)0.446CutaneousMean modified Rodnan skin score14.3 (0-51)17.4 (0-51)6.1 (0-24)0.001Gottron Papules27% (46/171)33% (41/124)11% (5)0.003Sclerodactyly78% (126/162)82% (98/119)65% (28/43)0.020Laboratory valuesElevated CK25% (30/122)30% (26/88)12% (4/34)0.041VascularTelangiectasia36% (56/154)44% (49/111)16% (7/43)0.001History of ulceration53% (91/173)61% (77/127)30% (14/46)0.001CardiacCardiac Involvement6% (10)2% (3)15% (7)0.002Patient Related OutcomesPhysician global disease activity(0-100) min -max35(0-90) n=14138(0-90) n=10825(0-80) n=330.002Physician global disease damage(0-100) min -max31(0-85) n=14034(0-85) n=10819(0-60) n=320.008Conclusion:Results from this large international cohort of jSSc patients demonstrate significant differences between dcjSSc and lcjSSc patients. According to the general organ involvement and physician global scores, the dcjSSc patients had significantly more severe disease. These observations strengthen our previous findings of the unique organ pattern of pediatric patients.Supported by the “Joachim Herz Stiftung”Disclosure of Interests:None declared.
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Crabtree, Robert H. "Progress in Inorganic Chemistry. Volume 43 Edited by Kenneth D. Karlin (Johns Hopkins University). Wiley: New York. 1995. vi + 621 pp. $125.00. ISBN 0-471-12336-6." Journal of the American Chemical Society 118, no. 28 (January 1996): 6806. http://dx.doi.org/10.1021/ja955350d.
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Falconer, J., J. A. Owens, E. Allotta, and J. S. Robinson. "Effect of restriction of placental growth on the concentrations of insulin, glucose and placental lactogen in the plasma of sheep." Journal of Endocrinology 106, no. 1 (July 1985): 7–11. http://dx.doi.org/10.1677/joe.0.1060007.
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ABSTRACT The effect of restricting placental growth on maternal glucose, insulin and placental lactogen was investigated in 16 ewes carrying singleton lambs. Uterine caruncles were removed from seven ewes (caruncle ewes) before pregnancy, resulting in reduced placental size and retarded intra-uterine fetal growth. The concentration of insulin in maternal plasma was similar in both control and caruncle ewes. The concentration of glucose was significantly higher in the caruncle than in the control ewes (3·26 ± 0·15 (s.e.m.) mmol/l, number of observations (n) = 9, vs 2·75 ± 0·1, n = 9, P<0·02, and 3·27 ±0·16, n = 7, vs 2·46± 0·11, n = 12, P<0·001, for the carotid artery and utero-ovarian vein respectively). The concentration of ovine placental lactogen (oPL) in the utero-ovarian vein was reduced in the caruncle compared with the control ewes (283± 65 μg/l, n = and 705±106 μg/l, n = 18, P<0·02, respectively). Restriction of placental growth by removal of endometrial caruncles similarly reduced the concentrations of oPL in maternal arterial plasma (231±54 μg/l, n = 9, and 621±96 μg/l, n = 18, P<0·002). Production of oPL by the placenta was also reduced by limiting placental growth to 30±11 μg/min, n = 8, compared with 133±43 μg/min, n = 15, P<0·05, for the controls. Production of oPL per gram of placenta in the caruncle group, although only 34% of the control value, was not reduced significantly. These observations are consistent with the hypothesis that oPL may be involved in the redirection of maternal glucose during pregnancy to maximize the amount available for the fetus. J. Endocr. (1985) 106, 7–11
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Chen, Yu-ming, Birgit Teucher, Xin-yi Tang, Jack R. Dainty, Kenneth K. C. Lee, Jean L. F. Woo, and Suzanne C. Ho. "Calcium absorption in postmenopausal Chinese women: a randomized crossover intervention study." British Journal of Nutrition 97, no. 1 (January 2007): 160–66. http://dx.doi.org/10.1017/s0007114507210141.
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The Ca intake and food sources of Chinese postmenopausal women are quite different from those of their Western counterparts. But, little information on Ca metabolism is available in Chinese populations. We determined true fractional calcium absorption (TFCA), true Ca absorption ( = TFCA × Ca intake,Va), urinary Ca excretion (Vu) and the difference betweenVaandVu(Va − u), in response to three dietary Ca intake levels. Twenty-one healthy postmenopausal Chinese women aged 49–64 years were recruited for this randomized crossover trial from a general community, Guangzhou, China. Subjects were randomly assigned to receive 0, 500 and 1000 mg Ca/d for 5 weeks separated by 2-week washout periods. TFCA using Ca stable isotopes, total urinary Ca excretion and Ca intake were determined after 4 weeks of adaptation. Mean values for total Ca intake (Vi) of the three phases were 391 (sd197), 880 (sd130) and 1382 (sd160) mg/d. On usual diet, TFCA,Vu,VaandVa − uwere 0·57 (sd0·12), 175 (sd59) mg/d, 216 (sd98) mg/d and 41 (sd99) mg/d, respectively. With the supplementations of 500 and 1000 mg Ca/d, TFCA significantly decreased to 0·52 (sd0·12) and 0·43 (sd0·13) (P < 0·001); whereas urinary Ca (P = 0·003),VaandVa − uincreased significantly (P < 0·001). Using a mixed-effects nonlinear regression model, it was estimated thatVa − uwas approaching a plateau when mean Ca intake reached 1300 mg/d. In conclusion, the present findings suggest postmenopausal Chinese women have high Ca absorption efficiency and a mean Ca intake of about 1300 mg/d is required to maximize theVa − u.
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Kumar, Shaji, Ian W. Flinn, Paul G. Richardson, Parameswaran Hari, Natalie Scott Callander, Stephen J. Noga, A. Keith Stewart, et al. "Novel Three- and Four-Drug Combination Regimens of Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide, for Previously Untreated Multiple Myeloma: Results From the Multi-Center, Randomized, Phase 2 EVOLUTION Study." Blood 116, no. 21 (November 19, 2010): 621. http://dx.doi.org/10.1182/blood.v116.21.621.621.
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Abstract Abstract 621 Background: Two- and three-drug regimens incorporating bortezomib (Velcade®, V), lenalidomide (Revlimid®, R), dexamethasone (D), or cyclophosphamide (C) have been shown to be effective and well tolerated in previously untreated multiple myeloma (MM). Combining all four drugs in a single regimen (VDCR) may further enhance efficacy. Published results from the phase 1 dose-escalation portion of the non-comparative, multi-center EVOLUTION study showed that the VDCR regimen was highly active and generally well tolerated (Kumar et al Leukemia 2010). Here we present updated results from the phase 2 portion of the trial, focusing on efficacy and safety of the VDCR, VDR, and VDC regimens. Methods: Previously untreated patients with measurable disease were randomized to one of four treatment groups receiving up to eight 21-d cycles of VDCR (V 1.3 mg/m2 d 1, 4, 8, 11; D 40 mg d 1, 8, 15; R 15 mg d 1–14; C 500 mg/m2 d 1, 8), VDR (VD as in VDCR but with R 25 mg d 1–14), VDC (VDC as in VDCR), or VDC-mod (as for VDC but with an additional dose of C on d 15) as induction therapy, followed by four 42-d maintenance cycles of V 1.3 mg/m2 (d 1, 8, 15, 22) (all treatment arms). Patients eligible for autologous stem cell transplant (SCT) could undergo stem cell mobilization any time after cycle 2 and SCT any time after cycle 4. The primary endpoint was the combined complete response (CR) + very good partial response (VGPR) rate; secondary endpoints included safety/tolerability, time to response, duration of response, progression-free survival, and rate of minimal residual disease (MRD) negativity. Responses were assessed according to International Myeloma Working Group (IMWG) uniform criteria using an automated computer algorithm. Adverse events (AEs) were graded using the CTCAE v3.0. Results: Patient characteristics were similar among the groups with respect to age, performance status, ISS stage, and proportion of patients with high-risk cytogenetic features. Patients received a median of 5, 6, 6, and 6 treatment cycles in the VDCR, VDR, VDC, and VDC-mod arms, respectively; 65%, 60%, 52%, and 47% of patients had dose reductions of any drug. In the VDCR, VDR, VDC, and VDC-mod arms, respectively, 52%, 62%, 58%, and 65% of patients completed treatment; 31%, 43%, 24%, and 41%, respectively, underwent SCT. In the phase 2 response-evaluable patients (n=132), all treatment regimens showed substantial efficacy, with CR+VGPR rates of 59% (VDCR), 50% (VDR), 41% (VDC), and 59% (VDC-mod) (Table) (includes pre-transplant responses only in SCT patients). Of MRD-assessed patients, 46% (21/46) of those who achieved CR (including sCR) or nCR were MRD-negative; 48% (10/21), 75% (9/12), 0% (0/7) and 33% (2/6) in the VDCR, VDR, VDC and VDC-mod arms, respectively. Median time to first response was similar across arms (range 1.6–1.8 months); median time to best response of CR+VGPR was 4.0 months (VDCR), 3.4 months (VDR), 5.1 months (VDC), and 3.1 months (VDC-mod). Median duration of response has not been reached in any arm to date. All treatment regimens were generally well tolerated. In the VDCR, VDR, VDC, and VDC-mod arms, at least one grade ≥3 AE was observed in 81%, 76%, 79%, and 88% of enrolled patients, respectively; serious AEs were experienced by 42%, 40%, 21%, and 41% of patients, and AEs resulting in study discontinuation were reported for 19%, 17%, 12%, and 6% of patients. The five most common all-grade AEs across all treatment groups were fatigue (range 47–67%), nausea (36–67%), constipation (40–62%), diarrhea NOS (42–65%), and neutropenia (19–52%). The incidence of grade ≥3 (grade ≥2) peripheral neuropathy (PN) was 13% (40%) in the VDCR arm, 14% (45%) VDR, 9% (48%) VDC, and 18% (41%) VDC-mod; there was no grade 4 PN. Rates of grade ≥3 neutropenia/thrombocytopenia were 42%/10% for VDCR, 7%/7% VDR, 36%/12% VDC, and 65%/18% VDC-mod. Conclusions: All regimens appear highly active and generally well tolerated in previously untreated MM patients. The four-drug combination did not result in a substantial increase in response rate and was associated with a modest increase in the incidence of hematologic toxicities. Continuous weekly C in the VDC regimen was associated with high response rates and rapid responses, comparable to the VDR and VDCR arms. Outcome data will be presented following longer follow-up. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding; Bayer: Research Funding. Off Label Use: Lenalidomide for treatment of newly diagnosed myeloma. Flinn:Millennium Pharmaceuticals, Inc.: Research Funding. Richardson:Celgene, Millennium, Novartis, Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Hari:Celgene: Research Funding. Callander:Millennium Pharmaceuticals, Inc.: Research Funding. Noga:Amgen: Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ortho-Centicor: Honoraria, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau. Stewart:Millennium Pharmaceuticals, Inc.: Honoraria, Research Funding; Celgene: Honoraria. Rifkin:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau; Dendreon: Speakers Bureau. Wolf:Millennium Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Genentech and Multiple Myeloma Research: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; OrthoBiotech: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau. Estevam:Millennium Pharmaceuticals: Employment. Mulligan:Millennium Pharmaceuticals, Inc.: Employment. Shi:Millennium Pharmaceuticals: Employment. Webb:Millennium Pharmaceuticals: Employment.
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TEDESCHI, L. O., A. CANNAS, S. G. SOLAIMAN, R. A. M. VIEIRA, and N. K. GURUNG. "Development and evaluation of empirical equations to predict ruminal fractional passage rate of forages in goats." Journal of Agricultural Science 150, no. 1 (July 20, 2011): 95–107. http://dx.doi.org/10.1017/s0021859611000591.
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SUMMARYThe objectives of the present paper were to develop and evaluate empirical equations to predict fractional passage rate (kp) of forages commonly fed to goats using chemical composition of the diet and animal information. Two databases were created. The first (development database) was assembled from four studies that had individual information on animals, diets and faecal marker concentrations over time (up to 120 h post-feeding); it contained 54 data points obtained from Latin square designs. The second (evaluation database) was built using published information gathered from the literature. The evaluation database was comprised of five studies, containing 39 data points on diverse types of diets and animal breeds. The kp was estimated using a time-dependent model based on the Gamma distribution with at least two and up to 12 (rumen)+one (post-rumen) compartments (i.e. G2G1–G12G1) developed from the development database. Statistical analyses were carried out using standard regression analysis and random coefficient model analysis to account for random sources (i.e. study). The evaluation of the developed empirical equation was conducted using regression analysis adjusted for study effects, concordance correlation coefficient and mean square error of prediction. Sensitivity analyses with the developed empirical equation and comparable published equations were performed using Monte Carlo simulations. The G2G1 model consistently had lower sum of squares of errors and greater relative likelihood probabilities than other GnG1 versions. The kp was influenced by several dietary nutrients, including dietary concentration or intake of components such as lignin, neutral detergent fibre (NDF), hemicellulose, crude protein (CP), acid detergent fibre (ADF) and animal body weight (BW). The selected empirical equation, adjusted for study effects, ($kp_{/{\rm h}} = 0{\cdot}00161 \times {\rm NDF}_{{\rm g/kg\,BW}}^{1{\cdot}503 \pm 0{\cdot}371} \times {\rm e}^{(0{\cdot}022 \pm 0{\cdot}0097 \times {\rm BW}_{{\rm kg}} - 0{\cdot}00375 \pm 0{\cdot}0013 \times {\rm NDF}_{{\rm g/kg \ DM}} )} $) had an R2 of 0·623 and root of mean square error (RMSE) of 0·0122/h. The evaluation of the adequacy of the selected equation with the evaluation database indicated no systematic bias (slope not different from 1), but a low accuracy (0·33) and a persistent mean bias of 0·0129/h. The sensitivity analysis indicated that the selected empirical equation was most sensitive to changes in dry matter intake (DMI, kg/d), BW(kg) and NDF (g/kg dry matter) with standardized regression coefficients of 0·98, −0·43 and −0·32, respectively. The sensitivity analysis also indicated that the greatest forage kp in goats is likely to be c. 0·0569/h. The comparison with a previously published empirical equation containing data on cattle, sheep and goats, suggested that the distribution of the present empirical equation, adjusted for mean bias, is wider and that kp of goats might be similar to cattle and sheep when fed high amounts of forage under confinement conditions.
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Bedoya, S. A. O., M. V. Souza, L. G. Conceição, M. I. V. Viloria, F. L. Valente, F. H. Loures, J. C. L. Moreira, and P. G. B. Coelho. "Quantificação do colágeno dérmico equino por duas técnicas morfométricas: contagem de pontos e segmentação de cor." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 71, no. 3 (June 2019): 761–69. http://dx.doi.org/10.1590/1678-4162-10487.
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RESUMO Os colágenos tipos I e III apresentam diferentes tonalidades de birrefringência em cortes histológicos corados com Picrosirius red e analisados em microscópio sob luz polarizada. Com base nessa propriedade, os colágenos podem ser quantificados por histomorfometria. Entretanto, são muitas as variáveis que podem afetar a distribuição das cores na imagem histológica, e a escolha adequada dos parâmetros de análise têm grande influência no resultado final. O objetivo deste trabalho foi comparar a quantificação histomorfométrica de colágeno em pele equina pela morfometria por contagem de pontos e pela segmentação de cor com diversas configurações, a fim de se determinar o melhor método de avaliação. Para a morfometria por contagem de pontos, foram utilizadas três gratículas diferentes (391, 588 e 792 pontos de interseções) e, para a segmentação de cor, seis combinações de hue e brightness no software ImageJ. Os valores foram submetidos ao teste de Friedman, seguido pelo teste de Tukey com 5% de significância. Os resultados demonstraram que a quantificação dos colágenos na gratícula de 792 pontos foi equivalente aos resultados da segmentação de cor com brightness de 1-255 e hue de 0-42 e 43-120 para os colágenos tipos I e III, respectivamente. Dessa forma, conclui-se que a análise automática da segmentação de cor, utilizando configuração adequada para brightness e hue, pode substituir a morfometria por contagem de pontos de forma confiável e segura.
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Muniz, Thiago Pimentel, Victor Hugo Fonseca Jesus, Victor Aurelio Ramos Sousa, malu barbosa, and Vladmir Claudio Cordeiro De Lima. "A modified recursive partitioning analysis for predicting overall survival in patients with non-small cell lung cancer and central nervous system metastases." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e20604-e20604. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e20604.
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e20604 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers. Most patients with NSCLC have metastases at diagnosis and 30-50% of them will present brain lesions during follow-up. Nonetheless, patients with central nervous system (CNS) spread are poorly represented in clinical trials and the management of this clinical scenario is not standardized. Prognostic tolls are needed to help to guide the best approach for these patients. Methods: Descriptive, analytical, retrospective, single center study. Patients > 18 years of age diagnosed with NSCLC who developed CNS metastases treated at AC Camargo Cancer Center from January 2007 to December 2017 were included. The primary endpoint was overall survival (OS). The secondary endpoint was intracranial progression-free survival (IC-PFS). An exploratory analysis of prognostic factors associated with OS was undertaken. The Kaplan-Meier method was used to calculate OS and IC-PFS. We used the Cox Proportional Hazard model to assess the prognostic role of clinical and pathological characteristics on IC-PFS and OS. Variables with p < 0.20 at univariate analysis were used to generate a multivariate model. A survival tree was generated based on the two most statistically significant variables in the multivariate model. A p < 0.05 was considered statistically significant. Results: 311 patients were included. Median age was 60 years-old (IQR 54-68), 72.6% had an ECOG performance status 0 or 1 and 18.3% had a driver mutation detected ( EGFR, ALK or ROS1). IC-PFS was 7.1 months (95%CI 6.1-8.6) and OS was 10.3 months (95%CI 8.7-13.1). At multivariate analysis, the two most statistically significant prognostic factors associated with poor OS were ECOG performance status 2-4 (HR 2.12; 95%CI 1.40-3.20; p < 0.01) and the absence of a known driver mutation (HR 3.30; 95%CI 1.50-3.87; p < 0.01). Based on the curves generated by the survival tree, a prognostic model was developed - the Modified Recursive Partitioning Analysis (mRPA). This model stratified our cohort in four subgroups with significantly different OS (3.1 to 43 months). mRPA was better than RPA and GPA to predict prognosis in our population. Conclusions: OS and IC-PFS in patients with NSCLC and CNS metastases were better than previously reported. However, prognosis is widely variable and is directed mainly by performance status and the presence of a driver mutation. We propose a new prognostic model that my help to guide the treatment of these patients in the future. This model needs external validation.
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Comer, M. B., D. L. Campbell, R. L. Rasmusson, D. R. Lamson, M. J. Morales, Y. Zhang, and H. C. Strauss. "Cloning and characterization of an Ito-like potassium channel from ferret ventricle." American Journal of Physiology-Heart and Circulatory Physiology 267, no. 4 (October 1, 1994): H1383—H1395. http://dx.doi.org/10.1152/ajpheart.1994.267.4.h1383.
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FK1, a ferret ventricular full-length cDNA clone, encodes a 654-amino acid protein with 98% identity to human K+ transient outward current (Ito)-like HK1 (Tamkun et al. FASEB J.5: 331-337, 1991). FK1 is detectable in ferret brain, atrium, left and right ventricle, and kidney but not in skeletal muscle, endothelial cells, aorta, and liver. In Xenopus oocytes, FK1 cRNA gives rise to a rapidly activating and inactivating Ito-like current, which is highly K+ selective (Na(+)-to-K+ permeability ratio = 0.003). Activation occurs over an approximately 50-mV range (-40 to +10 mV) and displays a sigmoid delay in onset with potential-dependent time constants that decrease with depolarization. Steady-state activation can be described with either a simple Boltzmann relationship [half-activation potential (V1/2) = -25 mV, slope (k) = 10 mV] or a Boltzmann relationship raised to either the third or fourth power (alpha 3: V1/2 = -43 mV, kappa = 13.1 mV; alpha 4: V1/2 = -48 mV, kappa = 13.6 mV, where alpha is the activation variable). Inactivation kinetics are biexponential, with the main fast time constant becoming independent of membrane potential depolarized to 0 mV. Steady-state inactivation can be described with a single Boltzmann relationship (V1/2 = -57 mV, kappa = 5.0 mV). Fast inactivation is removed by NH2-terminal deletions. Recovery from inactivation (-90 mV) is quite slow (half-time = 4.8 +/- 2.5 s). In 2 mM extracellular K+ concentration ([K+]o), FK1 tail currents display conventional deactivation behavior; however, in 98 mM [K+]o the tail currents display "reopening" behavior. These results suggest a molecular basis for the electrophysiological similarities between ferret and human ventricular Ito (Campbell et al. J. Gen. Physiol. 101: 571-601, 1993; Nabauer et al. Circ. Res. 73: 386-394, 1993).
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MURAYAMA, NOBUKO, AYU MATSUNAGA, LADDA TANGBANLUEKAL, SUWALEE TANTAWIWAT, and RYUTARO OHTSUKA. "EFFECTS OF ORAL CONTRACEPTIVE USE ON BODY MASS INDEX AND BLOOD PRESSURE AMONG FEMALE VILLAGERS IN NORTH-EAST THAILAND." Journal of Biosocial Science 35, no. 2 (April 2003): 243–61. http://dx.doi.org/10.1017/s0021932003002438.
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The use of contraceptives has become prevalent among females in Thailand in the past 20 years, and oral contraceptive use has been suggested to trigger changes in fat intake, energy expenditure, fat metabolism and blood pressure. Based on field investigations of 391 married women aged 20 years or over in Yasothon Province, North-east Thailand, this study aims to elucidate the effects of oral contraceptive use on body mass index (BMI: kg/m2 ) and blood pressure, taking into account reproductive histories and socioeconomic conditions. The proportion of obese (BMI> 25) subjects was high in the age groups 30–39, 40–49 and 50–59, accounting for, respectively, 39·4%, 51·1% and 48·5% of these populations. The proportion of women with hypertension (90/140 mmHg) was 23·7%, 18·5% and 26·2% in the 40–49, 50–59 and 60–69 age groups. Current contraceptive practices in the studied population included sterilization by operation, oral contraception and injection. These methods accounted for 43·0%, 12·8% and 8·2% of the population, respectively. Sociodemographic factors such as reproductive history, years of education and household income were not significantly related to BMI or to blood pressure (ANOVA with age adjustment). In contrast, oral contraceptive users had significantly higher BMIs and diastolic blood pressures (p<0·01, ANOVA with age adjustment). Multiple regression analysis also revealed that oral contraceptive use was a weak but significant contributing factor to both high BMI and blood pressure when sociodemographic factors were taken into account and controlled for statistically. It can thus be concluded that the use of contraceptive pills, which contain oestrogen and progestin and are provided free of charge to Thai women, tend to increase BMI and to elevate blood pressure.
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Fonseca, A. J. M., A. A. Dias-da-Silva, and A. L. G. Lourenço. "Effects of maize and citrus-pulp supplementation of urea-treated wheat straw on intake and productivity in female lambs." Animal Science 73, no. 1 (April 2001): 123–36. http://dx.doi.org/10.1017/s1357729800058124.
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AbstractTwo experiments with lambs given food indoors and individually penned were designed to study the effects of different levels of ground maize and citrus pulp as supplements of a diet based on urea-treated straw (5 kg urea per 100 kg straw) offered ad libitum over a period of 16 weeks (experiment 1) or 10 weeks (experiment 2). The voluntary intake, live-weight gain (LWG), organic matter digestibility (OMD), urinary allantoin-nitrogen (UAN) excretion and acetate clearance rate were measured. The lambs were blocked on weight and randomly assigned to the treatments described below. Ruminal outflow rate of the solid and liquid phases from the rumen were also measured in experiment 2.In experiment 1, 20 female lambs from the Ile-de-France breed, with an initial live weight (LW) of 43 (s.e. 3·3) kg were used. Wheat straw (WS) was supplemented with 50 g/kg of fish meal (FM) and with 0, 100, 200 or 300 g/kg of ground maize on a dry-matter (DM) basis (M0, M1, M2 and M3, respectively). In experiment 2, 25 female lambs from the Portuguese breed Churra-da-Terra-Quente, with an initial LW of 24·2 (s.e. 4·3) kg were used. The straw was offered ad libitum during 10 weeks and supplemented with 50 g/kg of FM and 0, 100, 200, 300, or 400 g/kg of dried citrus pulp on a DM basis (CP0, CP1, CP2, CP3 and CP4, respectively).During the experiments, all animals were moved to metabolism cages to measure OMD and UAN excretion. Two additional incubation studies were carried out with rumen fistulated rams (experiment 1) or cows (experiment 2) given the diets described above close to the maintenance feeding level.In experiment 1 daily straw DM intake linearly decreased (P < 0·05) from 21·6 to 17·7 g/kg LW and LWG linearly increased (P < 0·05) from 51 to 154 g/day for treatments M0, M1, M2 and M3, respectively. The rate of straw DM degradation was significantly decreased (P < 0·01) by maize supplementation. Straw OMD (kg/kg) was 0·562, 0·583, 0·547 and 0·520 and UAN (mg/day) was 620, 790, 854 and 859 for treatments M0, M1, M2 and M3, respectively. Acetate clearance rate, increased (P < 0·05) as the level of maize inclusion increased.In experiment 2 daily straw DM intake was 23·3, 25·8, 24·7, 23·5 and 18·6 g/kg LW per day and LWG was –9, 28, 44, 64 and 67 g/day for treatments CP0, CP1, CP2, CP3 and CP4, respectively. Supplementation significantly increased LWG (P < 0·001) but at the 400 g/kg level depressed straw DM intake. Straw OMD linearly decreased (P < 0·05) from 0·484 (CP0) to 0·428 (CP4) g/kg and UAN (mg/day) was 181, 303, 363, 384 and 392 for treatments CP0, CP1, CP2, CP3 and CP4, respectively. Rumen outflow rate of fibre particles was unaffected by supplementation while the outflow of liquid phase tended to be increased (P < 0·10). The rate of DM degradation was significantly reduced (P < 0·01) by citrus-pulp inclusion. Acetate clearance rate was unaffected (P > 0·05) by citrus-pulp supplementation.The results of these experiments demonstrate that supplementation of urea-treated straw with ground maize up to 200 g/kg or with citrus pulp up to 300 g/kg of the diet DM increased or did not depress straw intake, increased the supply of microbial protein and have no significant effect on straw digestibility. The efficiency of utilization of absorbed energy was apparently improved by maize but not by citrus-pulp supplementation.
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Harrison, Melissa, Beverly Bell, Allen Chauvenet, Joanne Kurtzberg, Bruce Camitta, and Meenakshi Devidas. "Testicular Relapse in Lesser, Standard, and High Risk Patients Treated with Frontline Therapy for Childhood ALL. Pediatric Oncology Group Protocols 9201, 9405, 9605, and 9406." Blood 108, no. 11 (November 16, 2006): 1863. http://dx.doi.org/10.1182/blood.v108.11.1863.1863.
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Abstract From 1984–94, testicular relapse (TR) was reported in 10–20% of boys with ALL. Addition of intermediate and higher dose methotrexate (MTX) in subsequent trials may have reduced this risk. Pediatric Oncology Group (POG) trials 9201, 9405, 9605, and 9406 for B-precursor ALL opened in 1994–6. Protocol 9201 enrolled 365 lesser risk, 9405: 158 standard risk, 9605: 601 standard risk, and 9406: 512 higher risk (total 1,636) boys with ALL. All studies used a common induction protocol of L-asparaginase, vincristine, and prednisone. Doxorubicin was added for higher risk (based on age, initial WBC, and CNS/testicular status). Overt testicular disease at diagnosis was present in only 7/512 (1.4%) boys, all on 9406; they later received radiation therapy to the testicles. After induction, patients were assigned to POG protocols based on NCI risk criteria. Patients on 9201 received 6 courses of IV MTX (1g/m2) during intensification and once or twice daily oral 6-MP during continuation. Patients on 9405 were randomized to 1 or 2.5 g/m2 IV MTX for 12 courses during consolidation and once or twice daily oral 6-MP during continuation. Patients on 9605 received 6 courses of 1g/m2 IV MTX in consolidation and were randomized to +/− 6 months of divided dose oral MTX during intensification and once or twice daily oral 6-MP during continuation. Study 9406 randomized to 6 courses of 1 or 2.5g/m2 IV MTX and to standard or high dose AraC during intensification. TR was overt (physical exam) or occult (biopsy). 99 boys had isolated or combined TR. 0/7 with testicular disease at diagnosis had TR. Of the boys with TR, only 3 did not receive a significant amount of the total therapy. Lesser risk patients had the lowest incidence of TR and lowest overall mortality rate of 1/11(9.1%). Higher risk patients had more relapses during therapy, 11/32(34%) and highest overall mortality rate of 13/32(40.6%). Isolated TR was more common than combined, except on 9406. Median time to TR off therapy was 7.5 months (range 1–52). Median age at relapse was 9.4 years (range 1.8–22). Mortality post any type of second relapse after TR was 60% compared to 25% for those without second relapse(p=0.0124). Table 1 9201 9405 9605 9406 # Pts. 365 158 601 512 # TR 11(3.0%) 13(8.2%) 43(7.1%) 32(6.3%) Isolated TR, ON Rx/OFF Tx 8(2.2%),1/7 7(4.5%),1/6 30(5.0%),4/26 16(3.1%),6/10 Combined TR, ON Rx/OFF Rx 3(0.8%),0/3 6(3.9%),2/4 13(2.2%),2/11 16(3.1%),5/11 Median(Range)# of mos. off Rx 5(2–46) 11(1–28) 7(1–52) 8(1–42) Median(Range)Age at Relapse (yrs.) 6(4.4–15.6) 8.1(1.8–22) 8.3(3.4–21) 12.4(3–20.4) Table 2 Type of TR Count(%) Second Relapse(%) Overall Mortality(%) *Other includes 6-TR+CNS and 1-TR+Subcutaneous mass in cheek. Isolated TR 61/99 (61.6) 18/61 (13.1) 18/61 (29.5) TR+Marrow 31/99 (31.3) 5/31 (16.1) 10/31 (32.3) TR+Other 7/99 (7.1) 2/7(28.6) 2/7 (28.6) Overall TR rate on these studies was approximately 6%. Risk stratification, augmentation of therapy and use of intermediate and high dose MTX may have contributed to this reduction.
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Masarova, Lucia, Naval Daver, Naveen Pemmaraju, Prithviraj Bose, Sherry Pierce, Taghi Manshouri, Jorge E. Cortes, Hagop M. Kantarjian, and Srdan Verstovsek. "Do Patients with Post-Essential Thrombocythemia and Post-Polycythemia Vera Differ from Patients with Primary Myelofibrosis?" Blood 126, no. 23 (December 3, 2015): 4069. http://dx.doi.org/10.1182/blood.v126.23.4069.4069.
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Abstract Introduction: Clinical characteristics of post-essential thrombocythemia/polycythemia vera myelofibrosis "post ET/PV-MF" are not well defined as for primary myelofibrosis "MF". Objective: We aimed to identify morphological, clinical and prognostic characteristics of patients with post ET/PV-MF seen at our center. Methods: Retrospective chart review of 1120 patients with MF - 766 primary MF, 354 post ET/PV-MF, who were referred to our institution between years 1984-2013 was performed; 92% presented after the year of 2000. Fisher's exact and Mann-Whitney test were used for categorical and continuous variables; Cox proportional hazard model and Kaplan-Meier curves with log rank test for correlation between the variables and survival. Survival analysis were calculated after censoring patients for stem cell transplantation "SCT" (n=92). Results: Overall median follow up was 36 months (0-411), 51% (n=573) patients had died. Progression to AML after median time of 32 months was not different between groups and occurred in 9.5% (n=106) patients over observation period of 5180 persons-years. Incidence rate was 3.4 cases per 100 persons-year. Causes of death were known in 55% of patients, and included progression of MF in 38% (n=122), infection in 27% (n=86), and other reasons with less than 10% occurrence (complications post SCT; secondary malignancy; other medical conditions). Demographics and disease characteristics are depicted in a table. 92% of patients were evaluable for karyotype; abnormalities were detected in 39% (n=404), of which 53% were unfavorable with monosomal (23%), complex (43%) and trisomy 8 (18%) being the most common. Molecularly high risk mutations "MHR" in genes ASXL1, EZH2, and IDH1/2 were positive in 35% of tested patients (n=161) regardless of presence of driver mutation. IPSS and DIPSS plus scores were similar between MF and post ET/PV-MF (with IPSS low in 8.7%, intermediate 1 in 19%, intermediate 2 in 28%, and high in 44%). By multivariate analysis, higher risk categories of IPSS and DIPSSplus predicted shorter overall survival "OS" for both cohorts (by DIPSSplus - high risk: HR 2.7, 95% CI 2.1-3.5; int-2: HR 1.6; 95% CI 1.3-2.0). Median OS stratified by IPSS was 160 (HR 1.8, 95%CI 1.0-3.0), 116 (HR 1.5, 95%CI 1.0 -1.5), 78 (HR 1.4, 95%CI 1.2-1.7) and 54 months, p=0.001. Univariate analysis identified age over 65, anemia, trombocytopenia, leukopenia, increased blasts, splenomegaly, constitutional symptoms, unfavorable karyotype, JAK2 mutation and triple negativity as predictors for inferior survival. Age over 65; hemoglobin below 10, platelets below 100 and peripheral blasts ≥1% showed significance for predicting OS by multivariate analysis. When stratified according to diagnosis, higher age, anemia, thrombocytopenia, high blasts, JAK2 positivity and triple negativity retained prognostic significance for MF whereas anemia, thrombocytopenia, and JAK2 mutation for post ET/PV-MF. Median OS was 73 months (range, 0.1-210) without difference between MF and post ET/PV-MF. Conclusion: Post ET/PV-MF does not appear to have substantial different clinical characteristics than primary MF. Table. Characteristics Total, number or median (% or range) MF, number or median (% or range) PET/PV-MF, number or median (% or range) Age 65 (20-89) 64 (20-88) 64 (27-89) Age > 65 552 (49) 367 (48) 185 (53) Males 675 (60%) 494 (65) 181 (51)* WBC 9.6 (0.4-361) 17.3 (5-19) 16.7 (5-18) WBC > 24 203 (18) 133 (18) 70 (20) WBC < 4 160 (14) 130 (17) 30 (8.5)* Plt 204 (3-2690) 237 (1-1364) 354 (6-2690)* Plt < 100 276 (25) 220 (29) 56 (16)* Hgb 10.5 (5-18) 10 (5-18) 11 (5-19)* Hgb < 10 462 (42) 329 (43) 133 (38)* Transfusion dependency 265 (24) 203 (27) 62 (18)* Blasts ≥ 1% 523 (47) 371 (49) 152 (43) Splenomegaly 668 (60) 459 (63) 209 (65) Symptoms 793 (71) 537 (70) 256 (73) LDH 1246 (189-10343) 1248 (189-10353) 1261 (205-8476) LDH > 620 958 (86) 640 (85) 318 (90)* JAK2 positive 586 (57) 371 (63) 215 (37)* MPL positive 19 (1.9) 16 (84) 3 (16)* CARL positive 53 (5) 27 (51) 26 (49)* Triple negative 26 (2.5) 21 (81) 5 (19)* *statistically significant differences (p<0.05) Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding.
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Wasan, Harpreet, Richard A. Adams, Richard H. Wilson, Cheryl Pugh, David Fisher, Ayman Madi, Bruce Sizer, Rachel Butler, Angela M. Meade, and Tim Maughan. "Intermittent chemotherapy (CT) plus continuous or intermittent cetuximab (C) in the first-line treatment of advanced colorectal cancer (aCRC): Results of the two-arm phase II randomized MRC COIN-B trial." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 536. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.536.
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536^ Background: COIN-B is a trial of intermittent chemotherapy (ICT) plus intermittent cetuximab (C) vs ICT plus continuous C in the first-line treatment of aCRC. It complements the COIN trial by investigating how C might safely and effectively be added to an ICT strategy. Methods: Patients (pts) had measurable aCRC; no prior CT for metastases; WHO PS 0-2 and good organ function. Randomisation was: Arm D - continuous OxFU + weekly C for 12 wks then a planned break from all therapy; Arm E - OxFU + weekly C for 12 wks then weekly C. Upon RECIST progression on either arm, OxFU (or FU) plus C was restarted and continued until progression on maximal tolerated therapy. Prospective KRAS testing was introduced in May 2008. Primary outcome measure is Failure-Free Survival (FFS) at 10 months (mo) in KRAS-wt pts who had not progressed, died or failed the treatment strategy within 3 mo of randomisation. The trial was powered to differentiate between a desired 10-mo FFS rate of 50% and a minimum of 35%, in 136 pts (168 allowing for drop-outs). Secondary outcome measures included safety, overall survival (OS) and toxicity. Results: 169 KRAS-wt pts were randomised 07/07 to 06/10, 77 arm D / 92 arm E. Median age 64 years (IQR 55-70); 92% PS 0-1. In Arms D and E respectively, 65 (84%) and 67 (73%) pts were eligible for the primary analysis; 10-mo FFS rates were 48% vs 54% (one-sided 95% confidence limit 37% and 43% respectively). Median FFS was 12.0 vs 13.7 mo respectively (IQR 6.1-20.3 and 8.6-23.2). Median OS was 20.1 vs 18.4 mo. First CFI length was 3.7 mo vs 5.1 mo (IQR 2.5-6.2 and 2.5-8.9). In pre-planned exploratory analysis, median time to progression/death after chemo break was 3.1 mo (IQR 2.1-8.1) in Arm D and 6.0 mo (IQR 2.9-10.9) in Arm E. Toxicity was similar and only 1 arm D pt had G 3 hypersensitivity following C reintroduction. Analyses by BRAF & NRAS (tested retrospectively) will be presented. Conclusions: C was safely incorporated in 2 ICT strategies. Continuous C as maintenance was associated with a longer CFI and longer time to progression/death. This encouraging strategy of incorporating biological maintenance therapy needs validation in phase III trials.
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Glassman, Danielle C., Avni Mukund Desai, Geoffrey Yuyat Ku, Jia Li, James J. Harding, Anna M. Varghese, Eileen Mary O'Reilly, and Kenneth H. Yu. "Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 471. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.471.
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471 Background: Therapy options for advanced pancreatic adenocarcinoma (PDAC) are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of N+F following progression on gemcitabine (G) based therapy (mPFS 3.1 mo, mOS 6.1 mo). There are limited additional data on the safety and efficacy of N+F following FDA approval in October 2015. We examined the post approval safety, tolerability and effectiveness of N+F in advanced PDAC patients at MSK. Methods: A retrospective chart review was conducted of all patients treated with N+F from Feb 2016 and ending in Aug 2017. Using the EMR and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of N+F, adverse events, PFS, OS and treatment response per RECIST. Results:N = 56 identified. Demographics: M/F 29/27, age 68 (range 42-88), prior lines of palliative chemotherapy (0/1/2/3/ > 3, 4/20/21/11). Median PFS was 2.9 months and median OS was 5.3 months. There was a significant difference in PFS, OS and prior lines of therapy between patients who previously progressed on irinotecan (N = 27) versus not (N = 29); PFS = 2.4 v 4.8 mo, p = 0.0154; OS = 3.9 v 8.4 mo, p = 0.0021; 2 v 1 line. ECOG score was not predictive of PFS or OS. There were 19 dose reductions (DR), most frequent reasons: fatigue (42%) and diarrhea (37%). Regarding RECIST: PR = 2 (4%), SD = 19 (34%). 10/43 (23%) experienced > 50% CA 19-9 reduction. Dose reductions were not associated with worse outcomes, in fact, patients with 1 or more DR experienced significantly longer PFS v none (DR 2, not reached; DR 1, 5.2 mo; DR 0, 2.5 mo, p = 0.0185). For the subset who received sequential therapy with G+nab-paclitaxel (P) followed by N+F (N = 25) mOS of 25.4 mo. Conclusions: These data support the safety and efficacy of N+F, re-inforcing results of NAPOLI-1. Patients whose disease previously progressed on irinotecan fared significantly worse than patients who did not, when treated with N+F. N+F appears active even in patients requiring DR. Sequential therapy with G+P followed by N+F demonstrates encouraging mOS. Collectively these findings underscore the utility of N+F in the therapy of advanced PDAC.
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Shanafelt, Tait D., Betsy R. LaPlant, Timothy G. Call, Daniel Nikcevich, Jose F. Leis, Wei Ding, Adam Pettinger, et al. "Randomized Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab with or without Concurrent Avastin for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)." Blood 124, no. 21 (December 6, 2014): 4673. http://dx.doi.org/10.1182/blood.v124.21.4673.4673.
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Abstract BACKGROUND: Although chemoimmunotherapy (CIT) has improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. Interactions with nurturing environments can enhance CLL B-cell resistance to apoptosis. These interactions include cytokine mediated prosurvival signals by angiogenic molecules, such as VEGF and bFGF that nurture CLL B-cells in an autocrine fashion and promote CLL cell survival partly through up regulation of anti-apoptotic proteins. These findings provide a strong rationale for testing anti-VEGF therapy in combination with a purine nucleoside analogue CIT regimen for upfront treatment. We conducted a randomized phase 2 CIT trial using pentostatin, cyclophosphamide, and rituximab with (PCR-B) or without (PCR) bevacizumab (B), an anti-VEGF monoclonal anti-body. METHODS: Eligible patients were previously untreated and had CLL in need of treatment by NCI-WG criteria (Blood 111:5446). Patients were randomized using a dynamic allocation procedure stratifying for stage (0-II vs. III-IV) and FISH (17p or 11q deletion vs. other) to receive either 6 cycles of rituximab (100 mg on day 1 of cycle 1; 375 mg/m2on day 2 of cycle 1 and day 1 of cycles 2-6) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) (PCR) administered every 21 days. Patients in the PCR-B cohort also received bevacizumab 15mg/kg on day 1 of cycles 1-5 and days 1, 22, & 43 of cycle 6. All patients underwent complete response evaluation 3 months after day 1 of cycle 6 (or last cycle of treatment for those completing < 6 cycles). MRD was assessed using 6-color flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 68 patients were enrolled through the Mayo Clinic Cancer Research Consortium between 1/2009 and 1/2013. Three patients were excluded from analysis: 1 patient canceled prior to treatment, 1 was dosed incorrectly, and 1 was ineligible due to immunophenotyping inconsistent with CLL. Median age of eligible patients was 63 years (range 43-81) and 43 (66%) were men. With respect to disease stage, 3 (5%), 38 (58%), and 24 (37%) had low, intermediate and high Rai stage disease. Eleven (17%) patients had deletion 17p or 11q & 29 (45%) had unmutated IGHV. No statistically significant differences were observed in these variables by treatment arm. All 65 evaluable patients have completed active treatment, with 54 (83.1%) completing the intended 6 cycles (PCR group 27/32 [84.4%] and PCR-B 27/33 [81.8%]). Hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 10 (31.3%) patients on PCR and 12 (36.4%) on PCR-B (p=0.79). Non-hematologic grade 3+ adverse events deemed at least possibly related to treatment were observed in 9 (28.1%) patients on PCR and 18 (54.4%) on PCR-B (p=0.04). The most common such events were hypertension (PCR: 3.1% vs. PCR-B: 21.2%), proteinuria (0% vs. 6.1%) and creatinine increase (3.1% vs. 6.1%). Across both arms, 64/65 (98.5%) patients achieved a response including 31/32 (96.9%) treated with PCR and 33/33 (100%) treated with PCR-B (p=0.49). CR/CRi was achieved in 10/32 (31.3%) patients treated with PCR & 18/33 (54.5%) treated with PCR-B (p=0.08). Of the 28 who achieved a CR/CRi, MRD analysis was completed on 26, of whom 12 (46%) were MRD negative. With respect to treatment arm, 5/32 (16%) patients on PCR and 7/33 (21%) on PCR-B achieved an MRD negative CR. Median time to retreatment for all 65 patients was 44.8 (95% CI: 34.6 – NA) months. Median overall survival has not yet been reached. With current follow-up no differences between treatment-free survival (p=0.38), progression-free survival (p=0.23), or overall survival (p=0.45) are observed by treatment arm. Plasma levels of angiogenic cytokines VEGF, bFGF, thrombospondin (TSP) and the chemokines CCL3 and CCL4 were measured prior to treatment and at the time of the post treatment response evaluation. Correlations of these cytokines with clinical outcome will be presented. CONCLUSION: The addition of bevacizumab to purine analogue-based CIT was generally well-tolerated and may increase complete remission rates in patients with CLL. No clear improvement in treatment free survival has been observed to date. Disclosures Shanafelt: Hospiria: Research Funding; Pharmacyclics/Jannsen: Research Funding; Cephalon: Research Funding; Celgene: Research Funding; glaxoSmithKline: Research Funding; Genetech: Research Funding; Polyphenon E Int'l: Research Funding. Off Label Use: Off label use of pentostatin for treatment of CLL. Off label use of bevacizumab for treatment of CLL. . Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.
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Cáceres Manrique, Flor De María, and Myriam Ruiz-Rodríguez. "Prevalencia de inicio tardío de la atención prenatal. Asociación con el nivel socioeconómico de la gestante. Estudio de corte transversal. Bucaramanga, Colombia, 2014-2015." Revista Colombiana de Obstetricia y Ginecología 69, no. 1 (March 28, 2018): 22. http://dx.doi.org/10.18597/rcog.3034.
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Objetivo: describir la prevalencia del inicio tardío de la atención prenatal y evaluar su asociación con el estrato socioeconómico donde habita la gestante.Materiales y métodos: estudio de corte transversal. Se incluyeron gestantes procedentes del área urbana de Bucaramanga, seleccionadas por muestreo por cuotas con afijación proporcional por estrato socioeconómico, según la clasificación socioeconómica del barrio donde habitan. Se consideró inicio tardío haber comenzado atención prenatal (APN) a las 12 semanas o más de gestación. Se evaluó asociación del inicio tardío con el estrato socioeconómico, controlando por variables sociodemográficas y clínicas de la gestante, y se elaboró un modelo de regresión log-binomial multivariada para estimar las razones de prevalencia con sus intervalos de confianza del 95 % (IC 95 %).Resultados: se incluyeron 391 gestantes, con edades entre 18 y 43 años, mediana 23 años; respecto a la escolaridad la mediana fue de 11 años con un rango entre 0 y 25 años. El inicio tardío se dio en el 29,7 % (IC 95 %: 25,2-34,5) de las gestantes. Estuvo asociado con estrato bajo, razón de prevalencias ([RP] = 1,57; IC 95 %: 1,08-2,56), falta de afiliación a la seguridad social al inicio del embarazo (RP = 2,73; IC 95 %: 2,04-3,67), la baja escolaridad (RP = 1,46; IC 95 %: 1,02-2,16) y la edad entre 18 y 24 años. Fueron factores protectores el recordar la fecha de la última regla (RP = 0,48; IC 95 %: 0,32-0,71) y tener pareja estable (RP = 0,82; IC 95 %: 0,64-0,98).Conclusiones: cerca de una de cada tres gestantes inicia tarde su APN. El inicio tardío está asociado con vivir en estrato socioeconómico bajo. Se requiere mejorar la captación temprana de las gestantes en esta población que presenta condiciones de inequidad en salud.
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Vasu, Sumithira, Maria Berg, Andreas Lundqvist, Muthalagu Ramanathan, Rebecca Lopez, Phil McCoy, Hua Zhang, Crystal Mackall, and Richard Childs. "A Highly Efficient Method to Expand CD3-CD56+ NK Cells from Cord Blood Segments." Blood 112, no. 11 (November 16, 2008): 3902. http://dx.doi.org/10.1182/blood.v112.11.3902.3902.
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Abstract Background: The infusion of in-vitro expanded cord blood derived CD3−CD56+ NK cells could potentially be used to enhance graft-vs-tumor effects following cord blood transplantation. In order to infuse NK cells derived from the same cord unit used during allogeneic transplantation, we sought to develop a highly efficient culture method to expand large numbers of NK cells in vitro from < 1 ml of cord blood. Methods: Immunomagnetic beads were used to deplete CD3+ T-cells from thawed cord blood. CD3 depleted mononuclear cells (<0.1% CD56+) were co-cultured with either irradiated EBV-LCL feeder cells or 41BB transduced K562 cells in X-VIVO 20, 10% human AB serum, and 500 IU/ml hrIL-2 for up to 47 days. Results: Day 12 EBV-LCL expanded NK cell cultures contained up to 90% CD3−CD56+ NK cells with less than 0.5% CD3+CD56+ cells. Expanded cord blood derived CD56+NK cells had similar expression of CD16, NKG2D, LFA-1, perforin, and granzymes A and B and had similar cytotoxic function as NK cells expanded from adult PBMC. Surface expression of NK cell TRAIL increased dramatically with in vitro expansion. By day 12, TRAIL surface expression by FACS was at similar levels observed on expanded adult NK cells, although expression gradually declined with prolonged cell culture; on days 12, 20, and 34, 89%, 57% and 11% of cord derived NK cells expressed TRAIL respectively. NK cell cultures expanded with 41BB-transduced APCs had a similar phenotype and cytotoxic function against K562 cells and renal cell carcinoma (RCC) cells as EBV-LCL expanded cells. Furthermore, NK cell cytotoxicity against RCC tumor targets treated with 10 nM bortezomib for 18 hrs (bortezomib upregulates RCC surface expression of DR5) was higher than untreated RCC cells confirming the functional cytolytic activity of TRAIL expressed on cord blood derived NK cells. We next evaluated the feasibility of expanding CD56+ NK cells from thawed segments attached to the umbilical cord blood units. TNC numbers of each segment ranged from 3–9 × 106 cells. Unmanipulated thawed segments were co-cultured with irradiated EBV-LCL feeder cells as described above. On Day 12, 43% of viable cells were CD3+, 21.5% were CD3+CD56+ and 36% were CD3− CD56+. CD3−CD56+ NK cells from thawed segments increased 200 – 300 fold with in vitro expansion when maintained in culture for 2–3 weeks (Table). To enrich for pure NK cell populations, subsequent expansions were performed on CD3 depleted cells pooled from three thawed segments stimulated with EBV-LCL; cultures on day 12 contained a pure population of CD3−CD56+ NK cells with virtually an identical phenotypic and cytotoxicity profile as NK cells expanded from larger aliquots taken directly from the thawed cord blood unit. By day 33, CD3−CD56+ NK cells expanded by up to 30,000 fold; in one experiment, 391 ×106 CD3-CD56+ NK cells were expanded from only 13,000 NK cells obtained from a pool of three thawed cord segments. Conclusions: In vitro-expansion of a pure population of CD3−CD56+ cells derived from cord blood can be achieved using EBV-LCL or 41BB transduced feeder cells. Expanded cells have increased NKG2D and TRAIL expression and enhanced TRAIL-mediated tumor cytotoxicity. Even with very low starting numbers of TNCs, substantial numbers of CD3+, CD3+56+ and CD3−CD56+ cells can be expanded in vitro from thawed segments using EBV-LCL feeder cells in advance of thawing of the cord unit. These methods are being optimized to allow for clinical scale expansion of NK cells from the same cord unit used for hematopoietic cell transplantation. Cell numbers after expansion of individual segments with EBV – LCL feeder cells Day 0 (×10e6) Day 16 (× 10e6) Fold expansion TNC 3–6 78–112 20–30 CD3+ 0.42–0.91 33–47 50–70 CD3+CD56- 0.015–0.032 16–24 700–1000 CD3-CD56+ 0.081–0.175 28–40 200–300 Cell numbers after CD3+ depletion of pooled segments and expansion with EBV – LCL feeder cells Day 0 (×10e6) Day 33 (× 10e6) Fold expansion TNC 4.16 401 96 CD3+ 0 0 - CD3+CD56- 0 0 - CD3-CD56+ 0.0132 391 29621
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Choi, Yong Won, Mi Sun Ann, Hyun Woo Lee, Seok Yun Kang, and Jin-Hyuk Choi. "Is surgical resection beneficial in recurrent or metastatic gastric cancer?" Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 4043. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.4043.
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4043 Background: Although chemotherapy is currently established as a standard treatment in recurrent or metastatic gastric cancer, the role of palliative surgical resection is still controversial. We investigated the survival benefit of surgical resection in patients (pts) with recurrent or metastatic gastric cancer who received systemic chemotherapy. Methods: A retrospective review was conducted on 698 pts who received palliative chemotherapy for recurrent (n = 307) or primary metastatic (n = 391) gastric cancer. Overall survival (OS) of pts who underwent surgical resection followed by chemotherapy was compared to that of pts who received chemotherapy alone. Results: Among 140 pts (primary metastatic: 97, recurrent: 43) with surgical resection, gastrectomy, metastasectomy, and gastrectomy with metastasectomy were performed in 83 (primary metastatic: 81), 44, and 13 pts, respectively. Higher surgical resection rate was observed in pts with young age ( < 70) (p = 0.010), ECOG PS 0 or 1 (p = 0.010), primary metastatic (p < 0.0001), absence of liver metastasis (p = 0.002), and signet ring cell histology (p = 0.002). The median OS of pts who underwent surgical resection before chemotherapy was significantly longer than that of pts who received chemotherapy alone (19 vs. 9 months, p <0.0001). The OS benefit of surgical resection was consistent across subgroups in terms of baseline characteristics including age, ECOG PS, disease status (primary metastatic vs. recurrent), peritoneal metastasis, and first-line chemotherapy regimen (single vs. combination). In multivariate analysis, surgical resection was independently associated with favorable OS (hazard ratio = 0.41, p < 0.0001) along with ≥second-line chemotherapy (p < 0.0001), whereas ECOG PS 2 or 3 (p = 0.013), signet ring cell histology (p < 0.0001), and peritoneal metastasis (p = 0.046) were independent prognostic factors of poor OS. Conclusions: The present study suggests that judicious use of surgical resection before chemotherapy in recurrent or metastatic gastric cancer pts may result in favorable outcome, although large scale phase III trials are essential to establish this treatment approach as a standard practice.
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Haugeberg, G., A. Kavanaugh, and B. Michelsen. "AB0783 THE IMPACT OF SKIN ITCHING ON HEALTH RELATED QUALITY OF LIFE IN PSORIATIC ARTHRITIS OUTPATIENT CLINIC PATIENTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1689.1–1690. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1088.
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Background:In psoriatic arthritis (PsA) both skin and musculoskeletal involvement can contribute to reduce health related quality of life (HRQoL) (1). Although itch is considered an important symptom in psoriasis, less is known about its extent and potential impact on HRQoL in PsA.Objectives:The aim of the study was to assess the prevalence of itchy, sore, painful or stinging skin in PsA patients and also to explore the impact of these symptoms on overall HRQoL and skin related HRQoL.Methods:PsA patients were consecutively recruited from a rheumatology outpatient clinic. Data collection included variables listed in the table. Patients also answered the question: “Over the last week, how itchy, sore, painful or stinging has your skin been? With answer alternatives: Not at all (score 0), a little (score 1), a lot (score 2) and very much (score 3)”. For analysis the variable was dichotomized; ‘Not at all’ and ‘a little’ were scored as ‘not itching’, and ‘a lot’ and ‘very much’ were scored as ‘itching’. HRQoL was assessed using the 15D questionnaire and skin HRQoL using the Dermatology Life Quality Index (DLQI). Categorical variables are presented as numbers and (%) and continuous variables as mean with (SD). An association with 15D and DLQI was explored using univariate and multivariate linear regression analysis.Results:Among 125 PsA patients (63 men and 63 women), means age was 52.2 years, BMI 28.3 kg/m2, disease duration 8.9 years; 15.2% were smokers. The number and percentage (%) of PsA patients reporting their skin to be itchy, sore, painful or stinging was as follows: Not at all 25 (20.0%), a little 71 (56.8%), a lot 23 (18.4%) and very much 6 patients (4.8%). The table shows data for all PsA patients and for patients defined to have no itching or having itching skin.Total (n=125)No itching (n=96)Itching (n=29)PAge (SD), years52.2 (10.1)52.3 (10.1)51.6 (10.2)0.73Women, n (%)62 (49.6%)49 (51.0%)13 (44.8%)0.56BMI (SD), kg/m228.3 (4.3)28.0 (4.0)29.4 (4.9)0.12Smoking, n (%)19 (15.2%)14 (14.6%)5 (17.2%)0.73Dis.dur. (SD), years8.9 (6.7)9.1 (6.7)8.0 (6.9)0.42CRP (SD), mg /L4.8 (8.5)4.4 (8.5)6.1 (8.5)0.37TJC68 (SD)9.70 (11.07)9.21 (10.32)11.39 (13.41)0.36SJC66 (SD)0.57 (0.99)0.56 (1.00)0.61 (0.96)0.84MASES (SD)2.9 (3.1)2.5 (2.9)4.0 (3.7)0.02IGA (SD), (VAS 0-100)14.0 (11.7)12.9 (10.2)17.8 (15.4)0.12PGA (SD), (VAS 0-100)35.3 (24.2)30.5 (22.6)50.9 (22.8)<0.01Pain (SD), (VAS 0-100)33.4 (23.4)28.6 (21.3)49.1 (23.6)<0.01Fatigue (SD), (VAS 0-100)45.1 (32.0)40.3 (31.7)61.0 (28.1)<0.01MHAQ (SD), (0-3)0.40 (0.35)0.35 (0.32)0.58 (0.39)<0.01PASI (SD), (0-72)2.4 (3.5)1.9 (3.2)4.1 (4.1)0.01DLQI (SD), (0-30)3.5 (3.6)2.2 (2.3)7.9 (3.9)<0.0115D (SD), (0-1)0.84 (0.09)0.86 (0.09)0.80 (0.08)<0.01bDMARDs, n (%)43 (34.7%)33 (34.7%)10 (34.5%)0.98csDMARDs, n (%)73 (58.4%)61 (63.5%)12 (41.4)0.03Dis.dur.: disease durationIn univariate analysis itching was found to be associated with impaired HRQoL assessed by 15D but not in adjusted analysis. In a regression model adjusting for age, gender, BMI and including variables with p<0.2 in univariate analysis (MASES enthesitis score, investigator [IGA] and patients global assessment [PGA], fatigue, pain, MHAQ, Psoriasis Area Severity Index [PASI] score and itching and treatment), only female gender, PASI score and itching were independently associated with reduced skin HRQoL.Conclusion:Skin itching was frequently reported in our PsA patients (20-25%) and was also found to be associated with impaired HRQoL, in particular for skin HRQoL (DLQI). The association was independent of the extent of skin involvement (PASI). More needs to be understood about subjective skin symptoms such as itch in order to improve HRQoL in PsA.References:[1]Kavanaugh A, et al. Ann Rheum Dis 2019;9:1215-9Disclosure of Interests:Glenn Haugeberg: None declared, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Brigitte Michelsen Grant/research support from: Research support from Novartis, Consultant of: Consulting fees Novartis
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Komrokji, Rami S., Amy E. DeZern, Katrina Zell, Najla H. Al Ali, Christopher Estling, Cassie Zimmerman, Wesley Hand, et al. "Validation of International Working Group (IWG) Response Criteria in Higher-Risk Myelodysplastic Syndromes (MDS): A Report on Behalf of the MDS Clinical Research Consortium (MDS CRC)." Blood 126, no. 23 (December 3, 2015): 909. http://dx.doi.org/10.1182/blood.v126.23.909.909.
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Introduction The primary goal for treatment of higher-risk MDS patients (pts) is to improve overall survival (OS) and delay acute myeloid leukemia (AML) evolution. The IWG 2006 response criteria are used in clinical trials and in clinical practice for assessing efficacy of MDS therapies. These criteria were originally proposed by an international group of experts based on available data and consensus. In an ad hoc landmark analysis of the AZA-001 study using the 2006 IWG criteria, pts who achieved hematological improvement (HI), complete response (CR), marrow CR (mCR), or partial response (PR) demonstrated improved OS. The aim of this study is to validate the IWG 2006 response criteria among a large cohort of higher-risk MDS pts. Methods Pts with higher-risk MDS (intermediate-2 (Int-2) or High Risk by International Prognostic Scoring System (IPSS)) who had received treatment and for whom details of response and outcome were available were included from the MDS CRC database. Pts were also classified per IPSS-R. The best response to treatment was categorized per the published IWG 2006 response criteria as CR, PR, mCR, HI, stable disease (SD) or progressive disease (PD). The primary endpoint was OS. Results We identified 646 treated higher-risk MDS pts. Table-1 summarizes baseline characteristics. The first line treatment was hypomethylating agent-based therapy (HMA) in 470 pts (74%). The median duration of follow up was 23.2 months (mo) (95% CI: (19.9, 26.5). Median OS from diagnosis was significantly longer for pts with int-2 IPSS risk disease IPSS (26.2 mo (21.5, 29.7)) compared to those who were High Risk (18.8 mo (15.9, 23.6); (p = 0.026). Median OS from diagnosis also differed by IPSS-R category (p < 0.001): for pts with Low risk (n = 6) it was not reached; Intermediate risk it was 41.7 mo (31.8, NR); High Risk it was 28.4 mo (24.1, 33.2); and for pts with Very High it was 16.5 mo (15.3, 19.1). The best IWG 2006 response rate for first line therapy among evaluable pts (n=597) was CR in 93 pts (16%), mCR in 10 (2%), PR in 57(10%), HI in 60 (10%), SD in 233 (39%), and PD in 144 (24%). The median OS based on IWG 2006 best response for first line therapy was 41 mo for CR, 12 mo for mCR, 26 mo for PR, 13 mo for HI, 14 mo for SD and 7 mo for PD. (p <0.001). CR was associated with better outcome compared to all other response groups. Pts with PR, HI, and SD had better outcome compared to PD, and similar outcome among the 3 groups. There was no difference in rate of AML transformation among response groups except in PD pts compared to others. For pts who were treated with HMA as first line therapy, the best response rates by IWG 2006 criteria were CR in 15%, mCR in 2%, PR in 10%, HI in 12%, SD in 40% and PD in 21%. Median OS in mo from time of HMA therapy based on response was: CR 19 (16.3, NR), mCR: 9 (7.1, NR), PR: 13 (8.8, NR), HI: 11 (7.7, 19.0), SD: 11.0 (8.5, 12.6), and PD: 3 (2.3, 3.9). (p <0.001) The best response by IWG 2006 criteria remained predictive of OS after adjusting for IPSS-R risk group. HR 0.30 (95% CI 0.2-0.4) for CR, and 0.57 (95% CI 0.45-0.7) for mCR/PR/HI compared to PD, (p <0.001) Conclusions: The best response by IWG 2006 criteria to first line therapy in higher-risk MDS correlates with OS. Pts who achieved CR had the best OS, while pts who achieved SD or better response had improved outcome compared to PD, with mCR having an OS equivalent to SD. The CR by IWG 2006 response criteria can be used as a surrogate endpoint for OS in higher-risk MDS pts in randomized Phase II studies determining comparison arms of Phase III trials, and for regulatory purposes. Table 1. Baseline characteristics Variable Total n=646 Age Median 68 Gender Male 399/645(62%) Race White 566/633 (89%) t-MDS Yes 161/545/514 (30%) WHO RA RARS RCMD RAEB-I RAEB-II MDS-U MDS/MPN CMML 5/527 (1%) 7/527 (1%) 69/527 (13%) 1153/527 (29%) 284/527 (54%) 3/527 (1%) 5/527 (1%) 1/527 (1%) IPSS Intermediate-II High 468/646 (72%) 178/646 (28%) R-IPSS Very low Low Intermediate High Very High 0 6/621 (1%) 74/621 (12%) 211/621 (34%) 330/621 (53%) IPSS karyotype Good Intermediate Poor 135/642 (21%) 118/642 (18%) 389 /642 (61%) IPSS-R karyotype Very good Good Intermediate Poor Very poor 7/642 (1%) 137/642 (21%) 134/642 (21%) 118/642 (18%) 246/642 (38%) Allogeneic transplant Yes 158/554 (29%) First line therapy HMA Chemotherapy IMiDClinical trial other 470/634 (74%) 57/634 (9%) 43/634 (7%) 25/634 (4%) 38/634 (6%) Lab (mean) Hgb (n=514) Platelets (n=514) ANC (n=514) Bone marrow blasts (n=639) 9.2 94 1.6 10% Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Incyte: Consultancy; Pharmacylics: Speakers Bureau; Celgene: Consultancy, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
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Schulman, Sam, Henry Eriksson, Ajay Kakkar, Clive Kearon, Sebastian M. Schellong, Patrick Mismetti, Martin Feuring, Stefan Hantel, Joerg Kreuzer, and Samuel Z. Goldhaber. "Influence of Age and Renal Function on Efficacy and Safety of Dabigatran Versus Warfarin for the Treatment of Acute Venous Thromboembolism: A Pooled Analysis of RE-COVER™ and RE-COVER™ II." Blood 124, no. 21 (December 6, 2014): 594. http://dx.doi.org/10.1182/blood.v124.21.594.594.
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Abstract Background: In the RE-COVER™ and RE-COVER™ II trials, dabigatran etexilate (DE) was as effective as warfarin (W) for prevention of recurrent venous thromboembolism (VTE) in patients with acute VTE, and was associated with a lower risk of bleeding. Objectives: Older patients and patients with renal impairment may be at greater risk of bleeding and/or VTE. In this post-hoc analysis of the pooled dataset from RE-COVER™ and RE-COVER™ II, we assessed rates of VTE recurrence and bleeding with DE and W in patients below and above 75 years according to renal function (normal, or mildly or moderately impaired). Methods: Patients with acute VTE, initially on parenteral anticoagulation, were randomized to either W (started in parallel; international normalized ratio range 2.0‒3.0) or DE 150 mg twice daily for 6 months. Primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death from randomization to the end of the prespecified post-treatment follow-up. Safety outcomes included centrally adjudicated major bleeding events (MBEs), the composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs), and any bleeds from the start of the double-dummy period (treatment with oral DE or W alone) to the end of the 6-month period. Patients with creatinine clearance (CrCL) ≤ 30 mL/min (hence not meeting inclusion criteria) were excluded from this analysis. Results: In all patients aged < 75 years, recurrent VTE/VTE-related death occurred in 65/2241 (2.9%) and 52/2218 (2.3%) patients with DE and W, respectively. In the analysis by renal function, event rates for DE vs W in subgroups with CrCL ≥ 80 (normal), 50–< 80 (mild renal dysfunction), and 30–< 50 mL/min (moderate renal dysfunction), respectively, were 3.1% (57/1828) vs 2.5% (45/1780), 2.1% (8/381) vs 1.5% (6/403), and 0% (0/32) vs 2.9% (1/35). In all patients aged ≥ 75 years, recurrent VTE/VTE-related death occurred in 3/272 (1.1%) and 10/304 (3.3%) patients with DE and W, respectively. Event rates for DE vs W in the normal, mild and moderate renal dysfunction subgroups, respectively, were 3.1% (1/32) vs 5.2% (3/58), 1.3% (2/158) vs 1.9% (3/158), and 0% (0/82) vs 4.5% (4/88). For the safety endpoints, in all patients aged < 75 years, MBEs occurred in (DE vs W, respectively) 16/2169 (0.7%) vs 29/2146 (1.4%) patients, MBEs/CRBEs in 87/2169 (4.0%) vs 153/2146 (7.1%) patients, and any bleeding in 303/2169 (14.0%) vs 430/2146 (20.0%) patients. The table shows event rates by renal function; bleeding rates in this age group were numerically lower for DE than W across all categories of renal function, except for rates of MBEs in patients with moderate dysfunction (6.7% vs 6.5%). Among the older patient group, bleeding event rates for DE vs W were 8/252 (3.2%) vs 11/287 (3.8%) for MBEs, 21/252 (7.9%) vs 35/287 (12.2%) for MBEs/CRBEs, and 48/252 (18.3%) vs 68/287 (23.0%) for any bleeding. The table shows event rates by renal function; the incidences of bleeding were numerically lower for DE vs W across all categories of renal function in older patients, except for MBEs (5.3% vs 3.6%) and MBEs/CRBEs (11.8% vs 9.6%) in the subgroup with moderate renal dysfunction. TablePatientsMBEsPatients, n/N (%)MBEs/CRBEsPatients, n/N (%)Any bleedsPatients, n/N (%)Age(year)CrCL (mL/min)DEWDEWDEW< 7530‒< 502/30 (6.7)2/31 (6.5)3/30 (10.0)4/31 (12.9)6/30 (20.0)8/31 (25.8)50‒< 805/359 (1.4)10/387 (2.6)26/359 (7.2)43/387 (11.1)70/359 (19.5)90/387 (23.3)≥ 809/1780 (0.5)17/1728 (1.0)58/1780 (3.3)106/1728 (6.1)227/1780 (12.8)332/1728 (19.2)≥ 7530‒< 504/76 (5.3)3/83 (3.6)9/76 (11.8)8/83 (9.6)15/76 (19.7)21/83 (25.3)50‒< 804/145 (2.8)6/149 (4.0)10/145 (6.9)23/149 (15.4)27/145 (18.6)35/149 (23.5)≥ 800/31 (0.0)2/55 (3.6)1/31 (3.2)4/55 (7.3)4/31 (12.9 )10/55 (18.2) Conclusions: In DE-treated patients, no increase in VTE recurrence was apparent for older (≥ 75 years) vs younger (< 75 years) patients. Recurrent VTE rates decreased with declining renal function. Bleeding events increased with declining renal function in both age groups irrespective of treatment, but in most subgroups were numerically less frequent with DE than with W. Disclosures Schulman: Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer HealthCare: Consultancy, Honoraria, Research Funding. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare: Consultancy; Boehringer Ingelheim (Canada): Consultancy. Schellong:Daiichi Sankyo: advisory boards, advisory boards Other, Honoraria; Bayer Healthcare: advisory boards, advisory boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Boehringer Ingelheim: advisory boards Other, Consultancy, Honoraria. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim: Employment. Kreuzer:Boehringer Ingelheim: Employment. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy.
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Metges, Jean-Philippe, Emon Elboudwarej, David Cunningham, Daniel V. T. Catenacci, Eric Van Cutsem, Zev A. Wainberg, Yafeng Zhang, et al. "Exploratory evaluation of baseline tumor biomarkers and their association with response and survival in patients with previously treated advanced gastric cancer treated with andecaliximab combined with nivolumab versus nivolumab." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 148. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.148.
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148 Background: Andecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9 (MMP9). Preclinical studies suggest that MMP9 inhibition relieves immune suppression and promotes T cell infiltration to potentiate checkpoint blockade. In the phase 2 study combining ADX with nivolumab (N) versus N monotherapy (NCT02864381), addition of ADX to N did not improve objective response rate, progression-free survival (PFS), or overall survival (OS). Methods: Archival tumor samples were collected from all patients (n = 141). CD8 and PD-L1 (28-8 DAKO) were assessed by immunohistochemistry. CD8+ cell density was measured in the tumor area. PD-L1 was prospectively scored by a pathologist for tumor cell (TC) and associated immune cell (IC) positivity. IFNg, Teffector (Teff), and activated CD8+ T cell (ActT) gene signatures were assessed by RNA sequencing. Due to a small number of responders, treatment arms were combined to evaluate response. Cox proportional hazards models were used for survival analyses. Nominal p-values are reported. Results: Baseline biomarkers of T cell infiltration and activation did not differentiate responders from non-responders (IFNg, Teff, ActT, CD8+; p > .10). None of the evaluated biomarkers were associated with PFS or OS for all treated patients or per treatment arm (IFNg, Teff, ActT; p > .10), with the exception of CD8+ (PFS HR = .43, p = .02). The majority of baseline samples were positive for IC PD-L1 (< 1%, n = 36; 1-10%, n = 50; > 10-25%, n = 32; > 25%, n = 20) and negative for TC PD-L1 (H = 0, n = 88; H < 1, n = 27; H > 1; n = 27). Comparing ADX/N to N, there was a trend toward longer OS for the PD-L1+ (TC + IC ≥ 1%) population (n = 102, HR = .621, p = .098), the TC H < 1 group (HR = .464, p = .08) and the IC > 10-25% (HR = .466, p = .08). Conclusions: Neither CD8+ cell density nor IFNg, Teff or ActT gene signatures were associated with response or survival to checkpoint blockade. While TC was low, IC intermediate and TC + IC ≥ 1% PD-L1+ groups trended toward better survival for the ADX+N arm, consistent with the hypothesis that ADX potentiates N activity; this did not translate into better outcome. Clinical trial information: NCT02864381.
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Kutluk, M. T., and M. A. Yeşilipek. "Pediatric Cancer Registry in Turkey (Turkish Pediatric Oncology Group & Turkish Pediatric Hematology Association)." Journal of Global Oncology 4, Supplement 2 (October 1, 2018): 67s. http://dx.doi.org/10.1200/jgo.18.25100.
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Background: Each year more than 200,000 new cancer cases are expected in children & adolescents aged 0-14 years at global level. Although the long term survival rates have been improved to 85% in high income countries, it is still lower than this LMICs with a wide range around the world. Pediatric registries are critical for planning for pediatric cancer care. This study summarizes the update of pediatric cancer registry in Turkey. Aim: To analyze the pediatric cancer distribution through Turkish Pediatric Cancer Registry for the years of 2009-2017. Method: Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Association established a Web based cancer registry in Turkey in 2002. The registry information for 2002-2008 was presented earlier. This study, now, is presents the distribution of pediatric cancers for the years of 2009-2017. International Childhood Classification System was used in classification. Basic demographic findings, ICD-O-3 morphology & topography codes were recorded for each cases. This is an update of the Turkish Pediatric Cancer Registry. Results: During the 9 years from 2009 to 2017, 14,769 pediatric cancer cases were recorded. For all cases, median age was 6.7 years (0-17 M/F 8318/6443, 3 hermaphrodite 5 unknown). Age distribution was 0-4 yrs, 40.8%; 5-9 yrs, 24.5%; 10-14 yrs, 23.3%; 15-19 yrs, 11.4%. The distribution of tumor types were [number of cases, percentage of total, median age years, M/F]: leukemia (4114, 27.9%, 5.5, 2366/1748); lymphoma and other RES tumors (2823, 19.1%, 9.6, 1904/914, 1 hermaphrodite 4 unknown); CNS [brain & spinal] (1950, 13.2%, 7.1, 1072/828); sympathetic system (1166, 7.9%, 2.4, 609/557); retinoblastoma (351, 2.4%, 1.4, 197/154); renal (736, 5.0%, 3.3, 345/391); liver (242, 1.6%, 1.8, 132/110); malignant bone (965, 6.5%, 12.6, 527/438); soft tissue sarcomas (991, 6.7%, 7.4, 580/411); germ cell (911, 6.2%, 8.2, 331/577, 2 hermaphrodite, 1 unknown); carcinoma and other malignant epithelial (436, 3.0%, 13.6, 212/224); other/nonspecific malignant (84, 0.6%, 7.1, 43/41) tumors. Five year survival rate was found as 67.8%. Conclusion: Registry provides the essential information for planning the pediatric cancer care. This registry became a critical source for health care professionals in Turkey since beginning. Survival rates for children increased to 67.8% based on this study. This is compatible with the survival rates from other upper middle income countries. This data also allows the comparison of the national data with the national and international studies. Investment on the pediatric cancer registry is one of the first steps of investments on pediatric cancer care.
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Vose, Julie M., Ravi Pingali, Nina Wagner-Johnson, Fausto R. Loberiza, Timothy S. Fenske, Sarah Jewell, Martin Bast, Nancy L. Bartlett, and James O. Armitage. "Lack Of Clinical Benefit For Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma In First Complete Remission." Blood 122, no. 21 (November 15, 2013): 4303. http://dx.doi.org/10.1182/blood.v122.21.4303.4303.
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Abstract Background The use of routine surveillance imaging (RSI) for patients in first complete remission (CR1) following front-line rituximab (R) based anthracycline therapy remains controversial. We compared patients with diffuse large B-cell lymphoma (DLBCL) who received an R-CHOP or a similar regimen, obtained a CR and then were followed by either RSI or clinical surveillance (CS) in which scans were only performed for signs or symptoms. Methods Patients from three tertiary care center from 2001-2011, who achieved a CR1 with frontline R-CHOP or similar therapy for DLBCL, and had a minimum follow up of 1 year were analyzed. Patients with HIV-related lymphoma, transformed lymphoma, and post-transplant lymphoproliferative disorders were excluded. Patients with composite lymphoma were included only if the DLBCL component was >50%. Patients were stratified into two groups based on the surveillance strategy employed. Baseline patient characteristics, prognostic features, treatment type, and outcomes were compared. Results 391 patients with DLBCL treated with R-CHOP or similar regimens who obtained CR1 were analyzed. There were 129 patients in the CS group and 262 in the RSI group. Patient characteristics (age, gender, stage, and IPI) were similar in the two groups. The median follow up is 5 years (range 1 – 12). Relapse after CR1 was detected in 26 (20%) of patients in the CS group and 46 (18%) of the RSI group. The median number of images in the CS group was 0 (range 0-14) and 4 (range 1-27) in the RSI group, p<0.0001. The median average number of images per year of follow up in the CS group was 0 (range 0-6) and 1 (range 1-13) in the RSI group, p<0.0001. Relapses were detected through clinical manifestations in 100 % of CS cases versus 43% in RSI cases, p=0.01. The 5 year progression-free survival (PFS) was 76% in the CS group and 82 % in the RSI group (p = 0.31). The 5 year overall survival (OS) was 87% in the CS group and 92 % in the RSI group (p=0.15). The table shows an analysis of OS by IPI and type of surveillance. Conclusions The majority of relapses in patients with DLBCL after achieving CR1 to an R-CHOP or similar regimen occur when signs or symptoms of the disease lead to evaluation and are not detected by RSI. Although asymptomatic relapses are occasionally detected by RSI, in this large cohort of patients neither a PFS nor OS benefit could be demonstrated in favor of RSI. Given the additional cost, radiation exposure and risk of additional procedures, we conclude that the use of RSI in patients with DLBCL in CR1 has limited clinical utility. Disclosures: No relevant conflicts of interest to declare.
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Ruiz, Maria Armila, David Shuey, Jin Han, Binal N. Shah, Richard Minshall, James P. Lash, Victor R. Gordeuk, and Santosh L. Saraf. "Haptoglobin 1-1 Isoform Predicts Higher Serum Haptoglobin Concentration and Lower Multiorgan Failure Risk in Sickle Cell Disease." Blood 138, Supplement 1 (November 5, 2021): 3095. http://dx.doi.org/10.1182/blood-2021-149697.
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Abstract Haptoglobin (HP) is the major scavenger of cell-free hemoglobin in circulation. When haptoglobin is depleted, cell-free hemoglobin can lead to organ damage through direct oxidative injury, upregulation of inflammatory pathways, and depletion of nitric oxide. A common polymorphism in HP gives rise to structurally and functionally distinct phenotypes: HP 1-1, HP 2-1, and HP 2-2. In people of African descent, the HP 1-1 and 2-1 phenotypes have been associated with higher serum HP concentrations compared to the HP 2-2 phenotype (PMID 10807979). In hemolytic diseases, such as sickle cell disease (SCD), the consequence of the HP polymorphism is unclear but could influence cell-free hemoglobin processing and susceptibility to organ damage. We first investigated whether the HP isoforms are associated with HP concentrations at steady-state. Between 10/2009 and 6/2018, we recruited 431 SCD patients into a longitudinal registry at our institution during a routine clinic visit, which we defined as steady-state. Baseline clinical and laboratory data were collected at the time of enrolment. The median age of the cohort was 32 (interquartile range [IQR], 24 - 43) years, 43% were male, 76% were SCD SS or Sβ 0-thalassemia genotype, and 46% were on hydroxyurea at the time of enrolment. Genotyping of the HP polymorphisms by PCR demonstrated the HP 1-1 isoform in 30% (n = 129), the HP 2-1 isoform in 47% (n = 203), and the HP 2-2 isoform in 23% (n = 99) of the SCD cohort. Serum samples were available in 244 of the 431 SCD patients at steady-state. Serum concentrations of HP, measured by ELISA, were higher in those with the HP 1-1 isoform compared to the HP 2-1 or 2-2 isoform (Figure). In a linear regression model, independent variables associated with steady-state serum HP concentration included SCD SS or Sβ 0-thalassemia genotype (β -1.8; 95% CI: -2.5 to -1.0; P < 0.001), LDH (natural log β -0.9; 95% CI: -0.2 to -1.6; P = 0.018), hydroxyurea use (β 0.6; 95% CI: 0.1 to 1.1; P = 0.02), and HP 1-1 isoform (β 0.5, 95% CI: 0 to 1.1; P = 0.049), adjusting for age and sex. Between 9/2020 and 5/2021, we collected an additional 38 serum samples from SCD patients during a hospitalization for vaso-occlusive crisis (VOC) and serum samples from 7 SCD patients during a hospitalization for acute chest syndrome. The HP 1-1 isoform was associated with higher serum HP concentrations during VOC and during acute chest syndrome compared to the HP 2-1 or 2-2 isoforms (Figure). Interestingly, the serum HP trended higher from steady-state to VOC and to acute chest syndrome in SCD patients with the HP 1-1 isoform (β +1.1, P = 0.085) but trended lower in those with the HP 2-1 or 2-2 isoform (β -0.5, P = 0.099). Next we tested whether the HP 1-1 isoform is protective against multi-organ failure during hospitalizations for acute chest syndrome. For the longitudinal analysis, we focused on SCD patients with > 6 months of follow up at our institution (n = 391). A multiorgan failure event was defined as organ dysfunction involving at least 2 of the following organ systems: lung, kidney, liver, or central nervous system (PMID 8109600). With a median follow up of 6.8 (IQR, 3.5 - 8.9) years, we observed an acute chest syndrome episode complicated by multiorgan failure in 14% (53/391) of SCD patients. A significantly lower proportion of SCD patients with the HP 1-1 isoform developed a multiorgan failure event versus those with the 2-1 or 2-2 isoforms (5.7% vs. 17.2%, respectively; P < 0.001). On logistic regression analysis, acute chest syndrome with multiorgan failure was associated with the HP 1-1 isoform (OR 0.3, 95% CI: 0.1 to 0.6; P = 0.002) and baseline LDH (natural log OR 2.7, 95% CI: 1.2 - 6.3; P = 0.02), after adjusting for age, sex, SCD genotype and hydroxyurea use. In conclusion, we demonstrate that the HP 1-1 isoform is independently associated with higher serum HP concentrations at steady-state as well as during hospitalizations for VOC or acute chest syndrome compared to the HP 2-1 or 2-2 isoforms. Furthermore, the HP 1-1 isoform is protective against developing the devastating multiorgan failure syndrome during acute chest syndrome episodes. Our findings highlight the clinical significance of the HP isoforms and cell-free hemoglobin scavenging in SCD. Future studies assessing HP induction and scavenging function based on HP isoform may help elucidate high-risk patients for aggressive measures, such as rapid initiation of exchange transfusion therapy or HP replacement therapy. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Douvali, Evdoxia, Menelaos Papoutselis, Emmanuil Spanoudakis, Eleytherios Moustakides, Emilia Tsakiroglou, Konstantinos Tsatalas, and Ioannis Kotsianidis. "Safety and Efficacy of Azacitidine in Myelodysplastic Syndrome (MDS) Patients with Mild and Moderate Renal Impairment." Blood 120, no. 21 (November 16, 2012): 1716. http://dx.doi.org/10.1182/blood.v120.21.1716.1716.
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Abstract Abstract 1716 Myelodysplastic syndrome patients with renal impairment (RI) were excluded for the approval trials of azacitidine, thus the optimal use of the latter in such patients is currently undefined. Only one single center, retrospective study addressed the efficacy and toxicity of azacytidine in patients with RI (Batty GN et al), but no comparative analysis between patients with or without RI has been performed yet. We retrospectively analyzed 42 MDS patients treated with azacitidine in a non-trial clinical setting. Patients were classified according to WHO as RAEB-II (n=18), AML/MDS (n=5), CMML-II (n=8), MDS/MPN (n=4), RAEB-I (n=3) and RCMD (n=3). All patients had normal hepatic function and ECOG performance status of 0–2. Glomerular filtration rate (GFR) was estimated using the MRDM or the Cockroft-Gault formulas depending on patient's weight. Response to therapy and toxicity were evaluated using the IWG 2006 response criteria for MDS and CTCAE 3.0, respectively. In all patients azacitidine was started at 75mg/m2 SC for 7 days on 28-day cycles. Significance of differences was assessed by Kruskal-Wallis, Chi square or Fisher Exact tests as appropriate. Kaplan-Meier method with log-rank test was used for survival analysis. Overall survival (OS) was defined as the time from first azacitidine administration to death from any cause and Event-free survival (EFS) as the time from first azacitidine administration to leukemic transformation or death. Table I lists patients' characteristics. Based on GFR levels 3 groups were defined: no RI (n=14), mild RI (n=16) and moderate RI (n=12). Median follow up and number of completed cycles for all patients were 9.5 (1–37.2) months and 5.5(1–29), respectively. No differences in response rates were observed among the 3 groups (Fig 1A), though hematological improvement was more frequent in patients with moderate RI (p=0.052). The median OS and EFS were similar among the no RI (20.2 and 15.5 months for OS and EFS, respectively), mild RI (17.1 and 16.3 months) and moderate RI (11.7 and 10.4 months) groups (Fig 1B). Also, patients in all groups experienced comparable rates of adverse events (Table II). No significant fluctuations in GFR were observed both during the first and the subsequent cycles of azacitidine, though patients with mild RI and two no RI patients displayed a transient decline in GFR on day 7 of the first cycle, which recovered afterwards without requiring dose and/or schedule adjustments (Fig 2). Our results provide the first evidence that azacitidine is effective and well-tolerated in patients with mild and moderate RI and, if confirmed by prospective randomized studies, advocate that such patients can be managed in an analogous fashion to patients with normal renal function. Table I. Patients' characteristics Parameter No RI (n=14) Mild RI (n=16) Moderate RI (n=12) p-value Age (median) 70.3 (52–79) 68.8 (59–79) 77 (65–81) 0.006 Sex (Male/Female) 10/4 13/3 8/4 0.665 Median GFR (ml/min /1.73m2) 93.5 (87–140) 66.5 (57–76) 40.5 (33–48) >0.001 Karyotype risk (Good/Intermediate/Poor) 7/5/2 5/2/9 4/6/2 0.052 IPSS risk group (Int-2/High) 9/4 7/7 7/3 0.492 WPSS risk group (High/Very high) 7/7 7/7 7/3 0.6 ANC(x 10 9 /L) 0.7 (0.08–13.3) 1.99 (0.05–15.5) 3.75 (0.74–6,3) 0.115 Hemoglobin (g/dl) 8.35 (6.1–10.1) 9.1 (6,8–11,5) 9.35 (6.2–12.8) 0.321 Platelets (x 10 9 /L) 139.5 (11–311) 64 (12–150) 51.5 (15–160) 0.178 Heavily transfused (Yes/No) 9/5 9/7 9/3 0.592 Median number of cycles 5.5 (1–29) 5.5 (1–24) 5 (1–21) 0.48 Median follow up time (months) 8.9 (4.9–37,2) 10.4 (1.2–35.3) 7.8 (1–22) 0.4 Table II. Toxicity and adverse events Parameter No RI (n=14) Mild RI (n=16) Moderate RI (n=12) p-value Neutropenia (grade 3/4) 8 (57%) 10 (62.5%) 6 (50%) 0.8 Thrombocytopenia (grade 3/4) 7 (50%) 12 (75%) 9 (75%) 0.269 Infections (grade 1/2) 3 (21.5%) 4 (25%) 3 (25%) 0.269 Infections (grade 3/4) 5 (36%) 9 (56%) 7 (58%) 0.535 Bleeding (grade 1/2) 1 (7%) 0 (0%) 1 (8%) 0.513 Bleeding (grade 3/4) 3 (21.5%) 7 (43%) 7 (58%) 0.152 Dose adjustments 3 (21.5%) 5 (31%) 4 (33%) 0.832 Discontinuation of treatment due to toxicity 4 (28.5%) 4 (25%) 7 (58%) 0.151 Hospitalization (times) 6 (0–16) 9 (1–15) 5.5 (1–10) 0.141 Hospitalization (days) 16.5 (0–34) 20 (10–43) 16 (4–34) 0.427 Figure 1. Response and outcomes Figure 1. Response and outcomes Figure 2. Kinetics of GFR in patients with moderate (A), mild (B) and no (C) RI. Figure 2. Kinetics of GFR in patients with moderate (A), mild (B) and no (C) RI. Disclosures: Kotsianidis: Genesis-Pharma: Honoraria, Research Funding.
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Economopoulou, Panagiota, Nikolaos Spiridon Spathas, George Papaxoinis, Maria Anastasiou, Maria Gkotzamanidou, Ioannis Kotsantis, Niki Gavrielatou, et al. "Clinical implications of hyperprogression with immune checkpoint inhibitors in patients with head and neck squamous cell carcinoma (HNSCC)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 6034. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.6034.
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6034 Background: Hyperprogressive disease (HPD) refers to paradoxical acceleration of tumor growth kinetics (TGK) after initiation of treatment with anti- PD-1/PD- L1 agents and has been reported across tumor types in 4-29% of patients using different definitions. Preliminary data suggest that HPD might affect response to subsequent therapies. Methods: We compared TGK prior and TGK upon immunotherapy (IO) in 62 patients (pts) with recurrent/metastatic (R/M) HNSCC treated with PD-1/PD-L1 inhibitors. The TGK ratio (TGKR, ratio of tumor growth velocity before and upon treatment) was calculated. The first imaging assessment was performed 3 months (mo) after IO initiation. HPD was defined as 1. Radiological HPD (TGKR≥2) or 2. Clinical HPD (Disease-related rapid clinical deterioration post IO). Results: After median follow-up of 12.3 mo (range, 0.4-28.1), 43 pts progressed and 38 died. Median PFS was 2.8 mo (95%CI, 2.2-3.4) and median OS 8.6 mo (95%CI, 4.2-12.9). HPD was observed in 16 pts (25.8%), while 15 pts had early PD (Time to Treatment failure, TTF < 3 mo) and 31 late PD (TTF > 3mo). Among 16 pts with HPD, 11 had radiological HPD and 10 had clinical HPD. 4 pts had both clinical and radiological HPD. Pts with late PD had median OS 11.3 mo (95%CI, 9.3-13.3), those with early PD 5.2 mo (95%CI, 3.1-7.3 months) and those with HPD 5.1 mo (95%CI, 4.4-5.9) (p < 0.005). Regarding post-progression OS, pts with late PD had median 11.3 mo (95%CI 0-22.8), those with early PD 2.5 mo (95%CI 0.6-4.4) and those with HPD 4.2 mo (95%CI 1.7-6.7) (p = 0.001). Pts with HPD had a trend for longer median post-progression OS compared to pts with early PD (p = 0.121). Median PFS with chemotherapy after immunotherapy failure was 3.0 mo (95%CI 2.4-3.6) for pts with late PD, 2.1 mo (95%CI 0.9-3.4) for pts with early PD and 6.1 mo (95%CI 3.0-9.3) for those with HPD (p = 0.040). HPD was associated with longer median PFS with chemotherapy compared to pts with early PD (p = 0.016), while the difference in median PFS with chemotherapy between pts with HPD and late progressors was non-statistically significant (p = 0.260). Conclusions: Radiological or clinical HPD was observed in 25.8% of patients with R/M HNSCC treated with IO. Early progression to immunotherapy is an important predictor of short survival, while HPD was associated with improved PFS to subsequent chemotherapy.
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Kubesch, A., L. Grimm, K. Stratmann, M. Knabe, N. Filmann, K. Sprinzl, J. Hausmann, and I. Blumenstein. "P548 Drug Survival in Patients with Inflammatory Bowel disease: An observational study." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S517. http://dx.doi.org/10.1093/ecco-jcc/jjab076.669.
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Abstract Background Although the therapeutic array has significantly widened, over the past decades predicting treatment persistence in IBD patients is still a challenge. In this study we collected longitudinal data to determine drug survival on the medications currently available for IBD. Methods Patients treated in the IBD outpatient clinic of the Goethe University Hospital were retrospectively analyzed. Laboratory parameters and data on treatment adherence were collected via the electronic patient file. We investigated how many patients continued on the respective substances after the induction period and after the 1-year mark. Results A total of 601 patients were included. 321 patients were female (53.4), 280 patients were male (46.6). The median age was 43 (range 19–86). The median disease duration was 14 years (range 1–52). 320 patients (53.2) suffered from CD and 281 (46,8) patients suffered from UC. 95 patients were treated with Infliximab (IFX) with a median duration of 912 days (20–5273). 91 patients (96.8) were still on IFX after the induction period. 73 patients (76.8) patients reached the 1-year mark. At the endpoint of this investigation, 39 patients (41.9) were still on IFX. 172 patients were started on Adalimumab (ADA) with a median of 1054 (48–4458) days on the medication. Of this collective, 172 (100%) patients continued on ADA after the end of the induction period. 136 patients (79.1) reached the 1-year mark. At the endpoint of this investigation, 90 patients (52.3) were still on ADA. Of the entire cohort, 124 patients were treated with Vedolizumab (VDZ) with a median of 745.50 (0-2204) days on the medication. After the induction period for this medication, 123 patients (99.2%) were still on VDZ. 89 patients (71.8%) achieved the 1-year mark. At the endpoint of this investigation, 82 patients (66.1%) were still on VDZ. Lastly, 66 patients were treated with Ustekinumab (UST) with a median duration of 720 days (50–1777). 64 patients (98.5%) achieved clinical remission. 48 patients (72.7%) achieved the 1-year mark. At the endpoint of this investigation, 54 patients (83.1%) were still on UST. As we provided longitudinal data some patients have been exposed to several medications which in part explains the lower patient numbers in the more recently approved drugs. Conclusion Conclusion: The majority of patients were still on the medication after the respective induction in all treatment groups. 1-year treatment persistence was higher for and ADA in comparison to VDZ and UST. Our study provides further evidence on drug survival in IBD and may aid in advising patients in this matter.
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Magnus, Dan, Santosh Bhatta, and Julie Mytton. "432 Establishing injury surveillance in emergency departments in Nepal: epidemiology and burden of paediatric injuries." Emergency Medicine Journal 37, no. 12 (November 23, 2020): 825.2–827. http://dx.doi.org/10.1136/emj-2020-rcemabstracts.7.
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Aims/Objectives/BackgroundGlobally, injuries cause more than 5 million deaths annually. Children and young people are a particularly vulnerable group and injuries are the leading cause of death in people aged 5–24 years globally and a leading cause of disability.In most low and middle-income countries where the majority of global child injury burden occurs, systems for routinely collecting injury data are limited. There is a continuing need for better data on childhood injuries and for injury surveillance.The aim of our study was to introduce a hospital-based injury surveillance tool – the first of its kind in Nepal and explore its feasibility. We undertook prospective collection of data on all injuries/trauma presenting to 2 hospital emergency departments to describe the epidemiology of paediatric hospital injury presentations and associated risk factors.Methods/DesignA new injury surveillance system for use in emergency departments in Nepal was designed and used to collect data on patients presenting with injuries. Data were collected prospectively in two hospitals 24 h a day over 12 months (April 2019 - March 2020) by trained data collectors using tablet computers.Abstract 432 Table 1Socio-demographic profile and characteristics of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020 (N=2696)CharacteristicsFrequencyGender Male 1778 Female 918 Age groups 0–4 years 653 5–9 years 866 10–14 years 680 15–17 years 497 Median year (IRQ) 8 (5 – 13) Ethnicity/caste Janajati 1384 Brahmin/Chhetri 892 Dalit 148 Madhesi 146 Muslim 74 Others 50 Unknown 2 Place where injury occurred Home/Compound 1576 Highway/road/street 636 School 233 Recreational area 138 Workplace 76 Other 37 Activities at the time injury occurred Leisure/Play 1889 Travelling (other than to/from school/work) 296 Work 202 Travelling (to/from school/work) 184 Education 42 Organised sports 11 Other 52 Unknown 20 Intent of injury Unintentional 2560 Intentional (self-harm) 61 Intentional (assault) 75 Unintentional (n=2560) Fall 912 Animal or insect related 728 Road traffic injury 356 Injured by a blunt force 201 Stabbed, cut or pierced 176 Fire, burn or scald 65 Poisoning 52 Suffocation/choking 36 Electrocution 12 Drowning and submersion 7 Other 13 Unknown 2 Self-harm (n=61) Poisoning 38 Hanging, strangulation, suffocation 12 Stabbed, cut or pierced 6 Injured by blunt object 4 Other 1 Assault (n=75) Bodily force (physical violence) 43 Injured by blunt object 18 Stabbed, cut or pierced 8 Pushing from a high place 2 Poisoning 2 Sexual assault 1 Other 1 Nature of injury (one most severe) Cuts, bites or open wound 1378 Bruise or superficial injury 383 Fracture 299 Sprain, strain or dislocation 243 Internal injury 124 Head Injury/Concussion 83 Burns 67 Other 115 Unknown 2 Not recorded 2 Severity of injury No apparent injury 125 Minor 1645 Moderate 813 Severe 111 Not recorded 2 Disposition Discharged 2317 Admitted to hospital 164 Transferred to another hospital 179 Died 21 Leave Against Medical Advice (LAMA) 11 Unknown 2 Not recorded 2 Note:Not recorded = missing cases95% CI calculated using one proportion test and normal approximation method in Minitab.Abstract 432 Table 2Distribution of injuries by age-group, sex and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups & Sex0 - 4 years5 - 9 years10–14 years15–17 yearsMaleFemaleTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 239 (26.2) 328 (36.0) 249 (27.3) 96 (10.5) 636 (69.7) 276 (30.3) 912 (100) Animal or insect related 175 (24.0) 260 (35.7) 190 (26.1) 103 (14.1) 470 (64.6) 258 (35.4) 728 (100) Road traffic injury 49 (13.8) 108 (30.3) 86 (24.2) 113 (31.7) 223 (62.6) 133 (37.4) 356 (100) Injured by a blunt force 54 (26.9) 74 (36.8) 49 (24.4) 24 (11.9) 150 (74.6) 51 (25.4) 201 (100) Stabbed, cut or pierced 20 (11.4) 56 (31.8) 49 (27.8) 51 (29.0) 127 (72.2) 49 (27.8) 176 (100) Fire, burn or scald 42 (64.6) 10 (15.4) 9 (13.8) 4 (6.2) 27 (41.5) 38 (58.5) 65 (100) Poisoning 33 (63.5) 6 (11.5) 5 (9.6) 8 (15.4) 26 (50.0) 26 (50.0) 52 (100) Suffocation/choking 24 (66.7) 5 (13.9) 2 (5.6) 5 (13.9) 20 (55.6) 16 (44.4) 36 (100) Electrocution 2 (15.7) 0 (0.0) 3 (25.0) 7 (58.3) 10 (83.3) 2 (16.7) 12 (100) Drowning and submersion 1 (14.3) 1 (14.3) 3 (42.9) 2 (28.6) 3 (42.9) 4 (57.1) 7 (100) Other 6 (46.2) 4 (30.8) 3 (23.1) 0 (0.0) 10 (76.9) 3 (23.1) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) 2 (100) Total 647 (25.3) 852 (33.3) 648 (25.3) 413 (16.1) 1702 (66.5) 858 (33.5) 2560 (100) Self-harm Poisoning 0 (0.0) 0 (0.0) 6 (15.8) 32 (84.2) 7 (18.4) 31 (81.6) 38 (100) Hanging 0 (0.0) 0 (0.0) 3 (25.0) 9 (75.0) 4 (33.3) 8 (66.7) 12 (100) Stabbed, cut or pierced 0 (0.0) 0 (0.0) 2 (33.3) 4 (66.7) 1 (16.7) 5 (83.3) 6 (100) Injured by blunt object 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (100) 0 (0.0) 4 (100) Other 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 1 (100) Total 0 (0.0) 2 (3.3) 13 (21.3) 46 (75.4) 17 (27.9) 44 (72.1) 61 (100) Assault Bodily force (physical violence) 3 (7.0) 1 (2.3) 11 (25.6) 28 (65.1) 37 (86.0) 6 (14.0) 43 (100) Injured by blunt object 2 (11.1) 8 (44.4) 4 (22.2) 4 (22.2) 13 (72.2) 5 (27.8) 18 (100) Stabbed, cut or pierced 1 (12.5) 0 (0.0) 2 (25.0) 5 (62.5) 7 (87.5) 1 (12.5) 8 (100) Pushing from a high place 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 2 (100) Poisoning 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0) 2 (100) Sexual assault 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Other 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Total 6 (8.0) 12 (16.0) 19 (25.3) 38 (50.7) 59 (78.7) 16 (21.3) 75 (100) Abstract 432 Table 3Association of injury location, nature and severity with age among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups0 – 4 years5 – 9 years10–14 years15–17 yearsTotalChi-SquareInjury characteristicsn (%)n (%)n (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 537 (34.1) 504 (32.0) 319 (20.2) 216 (13.7) 1576 (100) <0.001 Highway/road/street 85 (13.4) 196 (30.8) 190 (29.9) 165 (25.9) 636 (100) School 15 (6.4) 107 (45.9) 85 (36.5) 26 (11.2) 233 (100) Recreational area 9 (6.5) 44 (31.9) 55 (39.9) 30 (21.7) 138 (100) Workplace 1 (1.3) 4 (5.3) 19 (25.0) 52 (68.4) 76 (100) Other 6 (16.2) 11 (29.7) 12 (32.4) 8 (21.6) 37 (100) Total 653 (24.2) 866 (32.1) 680 (25.2) 497 (18.4) 2696 (100) Nature of injury Cuts, bites or open wound 328 (23.8) 506 (36.7) 314 (22.8) 230 (16.7) 1378 (100) <0.001 Bruise or superficial injury 81 (21.1) 99 (25.8) 118 (30.8) 85 (22.2) 383 (100) Fracture 48 (16.1) 101 (33.8) 112 (37.5) 38 (12.7) 299 (100) Sprain, strain or dislocation 48 (19.8) 78 (32.1) 72 (29.6) 45 (18.5) 243 (100) Internal injury 44 (35.5) 8 (6.5) 18 (14.5) 54 (43.5) 124 (100) Head Injury/Concussion 18 (21.7) 26 (31.3) 18 (21.7) 21 (25.3) 83 (100) Burns 42 (62.7) 9 (13.4) 10 (14.9) 6 (9.0) 67 (100) Other 41 (35.7) 38 (33.0) 18 (15.7) 18 (15.7) 115 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Severity of injury No apparent injury 39 (31.2) 45 (36.0) 26 (20.8) 15 (12.0) 125 (100) <0.001 Minor 419 (25.5) 535 (32.5) 406 (24.7) 285 (17.3) 1645 (100) Moderate 171 (21.0) 262 (32.2) 225 (27.7) 155 (19.1) 813 (100) Severe 23 (20.7) 23 (20.7) 23 (20.7) 42 (37.8) 111 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Abstract 432 Table 4Association of injury location, nature and severity with sex among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020SexMaleFemaleTotalChi-SquareInjury characteristicsn (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 979 (62.1) 597 (37.9) 1576 (100) <0.001 Highway/road/street 421 (66.2) 215 (33.8) 636 (100) School 176 (75.5) 57 (24.5) 233 (100) Recreational area 111 (80.4) 27 (19.6) 138 (100) Workplace 62 (81.6) 14 (18.4) 76 (100) Other 29 (78.4) 8 (21.6) 37 (100) Total 1778 (65.9) 918 (34.1) 2696 (100) Nature of injury Cuts, bites or open wound 959 (69.6) 419 (30.4) 1378 (100) <0.001 Bruise or superficial injury 246 (64.2) 137 (35.8) 383 (100) Fracture 200 (66.9) 99 (33.1) 299 (100) Sprain, strain or dislocation 154 (63.4) 89 (36.6) 243 (100) Internal injury 50 (40.3) 74 (59.7) 124 (100) Head Injury/Concussion 59 (71.1) 24 (28.9) 83 (100) Burns 27 (40.3) 40 (59.7) 67 (100) Other 79 (68.7) 36 (31.3) 115 (100) Unknown 2 (100) 0 (0.0) 2 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Severity of injury No apparent injury 81 (64.8) 44 (35.2) 125 (100) 0.048 Minor 1102 (67.0) 543 (33.0) 1645 (100) Moderate 533 (65.6) 280 (34.4) 813 (100) Severe 60 (54.1) 51 (45.9) 111 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Abstract 432 Table 5Distribution of injuries by outcome and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Outcome of injuryDischargedAdmittedTransferredDiedLAMAUnknownTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 787 (86.5) 65 (7.1) 53 (5.8) 0 (0.0) 4 (0.4) 1 (0.1) 910 (100) Animal/insect bite/sting 704 (96.7) 3 (0.4) 19 (2.6) 0 (0.0) 1 (0.1) 1 (0.1) 728 (100) Road traffic injury 260 (73.0) 47 (13.2) 44 (12.4) 5 (1.4) 0 (0.0) 0 (0.0) 356 (100) Injured by a blunt force 190 (94.5) 4 (2.0) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0) 201 (100) Stabbed, cut or pierced 165 (93.8) 8 (4.5) 3 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 176 (100) Fire, burn or scald 52 (80.0) 12 (18.5) 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 65 (100) Poisoning 30 (57.7) 4 (7.7) 16 (30.8) 1 (1.9) 1 (1.9) 0 (0.0) 52 (100) Suffocation/choking/asphyxia 24 (66.7) 4 (11.1) 6 (16.7) 1 (2.8) 1 (2.8) 0 (0.0) 36 (100) Electrocution 7 (58.3) 2 (16.7) 2 (16.7) 1 (8.3) 0 (0.0) 0 (0.0) 12 (100) Drowning and submersion 4 (57.1) 0 (0.0) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 7 (100) Other 12 (92.3) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 2237 (87.5) 150 (5.9) 150 (5.9) 11 (0.4) 8 (0.3) 2 (0.1) 2558 (100) Self-harm Poisoning 5 (13.2) 8 (21.1) 23 (60.5) 0 (0.0) 2 (5.3) 0 (0.0) 38 (100) Hanging 1 (8.3) 0 (0.0) 1 (8.3) 10 (83.3) 0 (0.0) 0 (0.0) 12 (100) Stabbed, cut or pierced 6 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (100) Injured by blunt object 4 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 17 (27.9) 8 (13.1) 24 (39.3) 10 (16.4) 2 (3.3) 0 (0.0) 61 (100) Assault Bodily force (physical violence) 34 (79.1) 5 (11.6) 3 (7.0) 0 (0.0) 1 (2.3) 0 (0.0) 43 (100) Injured by blunt object 18 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (100) Stabbed, cut or pierced 6 (75.0) 1 (12.5) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 8 (100) Pushing from a high place 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Poisoning 1 (50) 0 (0.0) 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Sexual assault 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 63 (84.0) 6 (8.0) 5 (6.7) 0 (0.0) 1 (1.3) 0 (0.0) 75 (100) Abstract 432 Figure 1Seasonal variation of injuries identified by the injury surveillance system over a year among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Results/ConclusionsThe total number of ED patients with injury in the study was 10,154.2,696 were patients aged <18 years. Most injuries in children were unintentional and over half of children presenting with injuries were <10 years of age. Falls, animal bites/stings and road traffic injuries accounted for nearly 75% of all injuries with some (drowning, poisonings and burns) under-represented. Over half of injuries were cuts, bites and open wounds. The next most common injury types were superficial injuries (14.2%); fractures (11.1%); sprains/dislocations (9.0%). Child mortality was 1%.This is the biggest prospective injury surveillance study in a low or middle country in recent years and supports the use of injury surveillance in Nepal for reducing child morbidity and mortality through improved data.CHILD PAPER: RESULTS SECTIONTotal number of ED patients: 33046Total number of ED patient with injury: 10154 (adult=7458 & children=2696)8.2% (n=2696) patients with injury were children aged <18 yearsHetauda hospital: 2274 (84.3%)Chure hill hospital: 422 (15.7%)
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Walsh, J. A., A. Ogdie, K. Michaud, S. Peterson, E. Holdsworth, S. Bruce Wirta, S. Meakin, S. D. Chakravarty, A. Schubert, and L. Gossec. "AB0818 SKIN INVOLVEMENT IN PSORIATIC ARTHRITIS (PsA) - THE INCREMENTAL IMPACT OF PSORIASIS ON QUALITY OF LIFE, DISABILITY AND WORK PRODUCTIVITY: REAL-WORLD SURVEY IN US AND EUROPE." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1711.2–1712. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5758.
Full textAbstract:
Background:PsA involves joint and skin symptom presentation that varies across patients. Differences in patients outcomes with joint only, and joint and skin involvement have not been extensively studied in a real-world setting.Objectives:To assess prevalence of joint only, and joint and skin disease in a real-world clinical setting, and to assess incremental impact of skin symptoms on quality of life (QoL), disability and work productivity.Methods:A cross-sectional survey in patients with PsA recruited by rheumatologists and dermatologists was conducted in France, Germany, Italy, Spain, UK and US. Data were collected Jun-Aug 2018 via physician-completed patient record forms and patient self-completed forms. Patients were compared by joint and skin involvement using parametric and non-parametric tests. Multiple linear regression analyses examined impact of incremental body surface area (BSA) on patient reported outcomes (PROs). Models controlled for gender, age, time since diagnosis, employment status, biologic DMARD use, BMI, number of joints affected.Results:Of 1,909 patients (539 US, 1,370 EU), 35% of patients had joint only disease, while 26%, 23%, and 16% experienced joint disease plus 1-3%, >3-10%, and >10% BSA respectively (Figure 1). Patients were comparable demographically (Table 1). After controlling for demographics and number of joints involved, results showed BSA independently and significantly impacted QoL, work productivity, disability (Table 2).Table 1.Comparison of patient demographic and disease characteristics by joint and skin disease involvementJoints only (n=673)1-3% (n=493)>3-10% (n=447)>10%(n=296)p-valueAge, mean (SD)49.2 (13.7)49.2 (13.2)47.6 (12.4)47.6 (13.8)0.09Male, n (%)379 (56.3)260 (52.7)248 (55.5)155 (52.4)0.53BMI, mean (SD)26.9 (4.9)26.8 (4.6)26.7 (4.2)26.5 (4.7)0.52Caucasian, n (%)621 (92.3)442 (89.7)399 (89.3)270 (91.2)0.41Full-time employment, n (%)391 (60.9)275 (57.7)259 (59.1)153 (53.1)0.01Biologic tx, n (%)420 (62.4)283 (57.4)218 (48.8)141 (47.6)<0.01Months since diagnosis, mean (SD)68.4 (76.2)56.7 (68.2)54.2 (67.3)52.1 (75.1)<0.01Current BSA %, mean (SD)0.01.7 (0.8)6.3 (2.0)21.3 (10.1)<0.01*66 swollen joint count, mean (SD)1.5 (3.6)2.1 (4.2)7.1 (11.1)6.9 (10.5)<0.01*68 tender joint count, mean (SD)2.1 (4.1)3.7 (6.4)6.0 (7.7)9.8 (10.0)<0.01*Calculated on available data, n=394Table 2.Incremental impact of BSA on PROsBSA in addition to joint involvementChange in predicted PRO valuesP valueEQ5D utility (n=656)Joint only (ref)0.851-3%-0.020.31>3-10%-0.06<0.01>10%-0.06<0.01EQ5D VAS (n=668)Joint only78.140.741-3%-0.580.03>3-10%-3.780.14>10%-3.04WPAI % overall work impairment (n=369)Joint only15.880.911-3%+0.32<0.05>3-10%+5.110.01>10%+7.51HAQ-DI (n=635)Joint only0.320.411-3%+0.04<0.01>3-10%+0.22<0.01>10%+0.27PsAID12 (n=642)Joint only1.660.031-3%+0.42<0.01>3-10%+1.22<0.01>10%+1.37α PRO key for worse outcome (range): EQ5D utility (0-1.0) = lower; EQ5D VAS (1-100) = lower; WPAI (0-100) = higher; HAQ-DI (0-3) = higher; PsAID12 (0-10) = higherConclusion:Two thirds of this sample of actively treated PsA patients have skin involvement. Over half would be considered moderate-severe (BSA >3%). After controlling for joint symptoms, results show that increasing skin involvement in PsA patients adversely impacts QoL, disability and work productivity.Disclosure of Interests:Jessica A. Walsh Grant/research support from: AbbVie, Pfizer, Janssen, Consultant of: AbbVie, Novartis, Eli Lilly and Company, UCB, Alexis Ogdie Grant/research support from: Pfizer to Penn, Novartis to Penn, Amgen to Forward/NDB, Consultant of: Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Corrona, Janssen, Eli Lilly, Novartis, Pfizer, Kaleb Michaud Grant/research support from: Janssen, Steve Peterson Employee of: Janssen Research & Development, LLC, Elizabeth Holdsworth Employee of: Adelphi Real World, Sara Bruce Wirta Employee of: Janssen-Cilag Sweden AB, Sophie Meakin Employee of: Adelphi Real World, Soumya D Chakravarty Shareholder of: Johnson & Johnson, Employee of: Janssen Scientific Affairs, LLC, Agata Schubert Employee of: Janssen-Cilag, Laure Gossec Grant/research support from: Lilly, Mylan, Pfizer, Sandoz, Consultant of: AbbVie, Amgen, Biogen, Celgene, Janssen, Lilly, Novartis, Pfizer, Sandoz, Sanofi-Aventis, UCB
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Horwitz, Steven M., James M. Foran, Michael Maris, Ahmed Sawas, Craig Okada, Tatyana A. Feldman, Mark D. Minden, et al. "Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies." Blood 136, Supplement 1 (November 5, 2020): 41–43. http://dx.doi.org/10.1182/blood-2020-136198.
Full textAbstract:
Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging Fcγ receptors. Here we report updates from the first-in-human study of TTI-621 (NCT02663518) in hematologic malignancies. Methods Study Part 1 tested increasing weekly intravenous doses of TTI-621 based on 3+3 escalation. The maximum tolerated dose was initially determined to be 0.2 mg/kg based on dose limiting toxicity (DLT) of thrombocytopenia [Grade (Gr) 4 of any duration]. Expanded testing followed in patients (pts) with hematologic malignancies, including leukemia, lymphoma, and multiple myeloma. In Part 2, most pts received 0.2 mg/kg. However, based on investigator discretion, a subset of pts received escalating doses up to 0.5 mg/kg. In Part 3, pts with T-cell lymphomas received stepwise dose escalations from 0.2 to 0.5 mg/kg over the first 5−8 weeks. In over 200 pts tested in Parts 1−3, thrombocytopenia did not increase with dose, typically recovered within 2−4 days, and was not associated with clinical sequelae. Part 4 was then undertaken to optimize TTI-621 dosing and is currently escalating doses in a 3+3 manner through pre-planned dose levels (0.5, 0.7, 1, and 1.4 mg/kg) in pts with cutaneous T-cell lymphoma (CTCL). The DLT criteria was modified to require Gr 4 thrombocytopenia lasting >72 hours. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) per CTCAE v 4.03. Blood samples are obtained for pharmacokinetics (PK) and for pharmacodynamic (PD) assessments of receptor occupancy (RO) on normal peripheral T cells. Disease assessments are performed per Olsen's criteria. Results In Parts 1−3 (n=214), the most common related AEs were infusion-related reaction (IRR, 43%; 3% Gr ≥3), thrombocytopenia (30%; 22% Gr ≥3), chills (21%; 0% Gr ≥3), and fatigue (15%; 1% Gr ≥3). Objective responses to single agent TTI-621 were achieved in 14/71 (20%) NHL pts including CTCL (n=42, 1 CR, 7 PRs), PTCL (n=22, 2 CRs, 2 PRs) and DLBCL (n=7, 1 CR, 1 PR). In Part 4, as of July 10, 2020, 15 pts (9M/6F, median age 67 years) have enrolled into 4 dose cohorts (0.5−1.4 mg/kg). CTCL subtypes include mycosis fungoides (MF, n=10) and Sézary syndrome (n=5) with advanced (≥IIB) disease in 9 (60%) pts who received a median of 3 (range 1−12) prior systemic therapies. Related AEs have occurred in 11 (73%) pts including IRR (n=10) and thrombocytopenia (n=3); Gr ≥3 AEs have occurred in 4 (27%) pts including thrombocytopenia (n=3), IRRs (n=2), and exfoliative dermatitis (n=1). Thrombocytopenia generally occurred on dosing days, recovered in 2-4 days, and has not worsened with increasing doses. IRRs typically occurred during initial infusions. The Gr 3 IRR events occurred in 2 pts in the 1 and 1.4 mg/kg cohorts; low Gr IRRs have occurred across doses in 8 pts. IRRs typically resolved without recurrence and low Gr events often resolved allowing for completion of infusions. For initial infusions, the Gr 3 IRRs prompted increasing infusion times from 1 hour up to 4 hours and discretional use of steroid pre-medication. The exfoliative dermatitis occurred Day 80 and led to treatment discontinuation in 1 pt with MF whose underlying disease confounded the etiology. PK results reveal dose dependent increases in exposure; PD studies indicate ~60% RO at end of infusion up to 1 mg/kg. Antitumor activity to date includes 1 PR and 1 skin CR in 6 evaluable pts in the 1 mg/kg cohort; 2 responding pts bridged to allogeneic transplantation. The mean % change in mSWAT scores were -0.4%, -27%, and -37% for 0.5, 0.7 and 1 mg/kg cohorts, respectively. 1.4 mg/kg cohort results will be presented at the meeting. Conclusions In Parts 1−3, TTI-621 doses of 0.05 to 0.5 mg/kg were well-tolerated and demonstrated single agent activity in multiple hematologic malignancies. Preliminary data from Part 4 dose optimization indicate that weekly infusions of TTI-621 up to 1.4 mg/kg are well-tolerated without dose limiting or cumulative thrombocytopenia. Antitumor activity was seen at 1 mg/kg; dose escalation is continuing at 2 mg/kg. Disclosures Horwitz: Janssen: Consultancy; Verastem: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; GlaxoSmithKline: Consultancy; ASTEX: Consultancy; Portola: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Myeloid Therapeutics: Consultancy; Vividion Therapeutics: Consultancy; Infinity/Verastem: Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Affirmed: Consultancy; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Innate Pharma: Consultancy; Forty Seven: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kura Oncology: Consultancy; Miragen: Consultancy; Mundipharma: Consultancy. Foran:Agios: Honoraria, Research Funding; H3Biosciences: Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy. Sawas:Flatiron Health: Current Employment; Gilead: Speakers Bureau; Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Affimed: Research Funding; Roche: Current equity holder in publicly-traded company. Feldman:AstraZeneca: Consultancy; Viracta: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Janssen: Speakers Bureau; Bayer: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Portola: Research Funding. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees. Mei:Sanofi: Consultancy; Morphosys: Membership on an entity's Board of Directors or advisory committees. Flinn:Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Agios: Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Genentech, Inc.: Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Curio Science: Consultancy; Constellation Pharmaceuticals: Research Funding; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Loxo: Research Funding; BeiGene: Consultancy, Research Funding; Calithera Biosciences: Research Funding; Johnson & Johnson: Other; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding; Merck: Research Funding. Villa:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; AZ: Consultancy, Honoraria, Research Funding; Kite/Gilead: Consultancy, Honoraria; Nano String: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Sandoz Canada: Consultancy, Honoraria; Immunovaccine: Consultancy, Honoraria; Purdue Pharma: Consultancy, Honoraria. Percival:Pfizer: Research Funding; Trillium: Research Funding; Nohla Therapeutics: Research Funding; Biosight: Research Funding; Oscotec: Research Funding; Cardiff Oncology: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Debiopharm Group: Research Funding. Savage:Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie, Servier: Consultancy; Roche (institutional): Research Funding; Merck, BMS, Seattle Genetics, Gilead, AstraZeneca, AbbVie: Honoraria; BeiGene: Other: Steering Committee. Akilov:Mallinckrodt: Consultancy; Medivir: Consultancy; Seattle Genetics, Inc.: Consultancy; Kyowa Hakko Kirin: Consultancy; Soligenix: Honoraria; Pfizer: Research Funding; Actelion: Consultancy, Research Funding; Trillium Therapeutics Inc.: Consultancy, Research Funding. Diefenbach:Trillium: Research Funding; Millenium/Takeda: Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; MEI: Research Funding; LAM Therapeutics: Research Funding; Incyte: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Denovo: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Kim:Kyowa-Kirin Pharma: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Medivir: Membership on an entity's Board of Directors or advisory committees; Horizon Pharma: Consultancy, Research Funding; Merck: Research Funding; miRagen: Research Funding; Trillium: Research Funding; Galderma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Research Funding; Elorac: Research Funding; Forty Seven Inc: Research Funding; Neumedicine: Consultancy, Research Funding; Innate Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Solingenix: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Portola: Research Funding. Lin:Trillium Therapeutics Inc.: Current Employment. Catalano:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Molloy:Trillium Therapeutics Inc.: Current Employment. Large:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Ansell:Affimed: Research Funding; Bristol Myers Squibb: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; AI Therapeutics: Research Funding.
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Shanafelt, Tait D., Kari G. Chaffee, Timothy G. Call, Sameer A. Parikh, Susan M. Schwager, Wei Ding, Jose F. Leis, Asher Chanan-Khan, Susan L. Slager, and Neil E. Kay. "Atrial Fibrillation in Patients with Chronic Lymphocytic Leukemia (CLL)." Blood 126, no. 23 (December 3, 2015): 2950. http://dx.doi.org/10.1182/blood.v126.23.2950.2950.
Full textAbstract:
Abstract BACKGROUND: Consistent with the advanced age at diagnosis (median age ~70 years), most patients with CLL have co-existent health problems. These co-morbidities influence the ability of many CLL patients to tolerate aggressive chemotherapy-based treatment and can also contribute to treatment-related side effects. The recent development of novel signaling inhibitors, particularly the Bruton's tyrosine kinase inhibitor ibrutinib, has been a major treatment advance for patients with CLL. While these agents generally have favorable toxicity profiles relative to standard chemotherapy-based treatments, they are chronic therapies which patients typically stay on for an extended period. Preliminary data suggests ibrutinib may be associated with an increased risk of atrial fibrillation (Afib). In one randomized trial comparing ibrutinib to ofatumumab in patient with relapsed CLL, incident grade 3+ Afib occurred in 3% of ibrutinib treated patients compared to 0% of ofatumumab treated patients (NEJM 371:213). Despite these observations, the baseline frequency of Afib in patients with CLL is not well described - particularly incident atrial fibrillation acquired during the course of the disease. METHODS: We used the Mayo Clinic CLL database to evaluate the prevalence of Afib at the time of CLL diagnosis as well as the incidence of Afib during follow-up. All patients with a new diagnosis of CLL after January 1995 who were seen at Mayo within 12 months of diagnosis were included in the analysis. Afib was identified by chart review and by billing search using ICD9 codes. Data on co-morbid conditions associated with risk of Afib was also abstracted (e.g. hypertension, coronary artery disease [CAD], valvular heart disease, cardiomyopathy, diabetes mellitus, pulmonary disease). RESULTS: A total of 2444 patients with newly diagnosed and previously untreated CLL were seen at Mayo Clinic within 12 months of diagnosis between 1/1995 and 4/2015.Median age at diagnosis was 65 years and 1626 (66.5%) patients were men. A history of Afib was present at the time of CLL diagnosis in 148 (6.1%) patients. Four additional patients had Afib documented in the record but the precise date of onset (e.g. prior to or after CLL diagnosis date) could not be determined. Age, male sex and history of CAD, valvular heart disease, cardiomyopathy, hypertension, and diabetes were associated with a greater likelihood of having a history of Afib at the time of CLL diagnosis (all p<0.01). Among the 2292 patients without a history of Afib at CLL diagnosis, 139 (6.1%) had incident Afib during the course of follow-up for their CLL. The incidence of Afib among patients without a history of Afib at diagnosis was approximately 1%/year (Figure 1A). Considering both Afib present at the time of CLL diagnosis or acquired during the course of the disease, 291 (11.9%) of the 2444 patients in this cohort experienced Afib (median follow-up: 59 months). Among patients without Afib at the time of CLL diagnosis, the following characteristics at the time of CLL diagnosis were associated with an increased risk of incident Afib on multivariate analysis: older age (age 65-74 HR=2.4, p<0.001; age ≥75 HR=3.6, p<0.001), male sex (HR=1.8, p=0.004); valvular heart disease (HR=2.4, p=0.007), and hypertension (HR=1.5; p=0.02). A predictive model for acquired Afib was subsequently constructed based on the independent factors in the Cox regression model. An individual weighted risk score was assigned to each independent factor based on the regression coefficients of the HRs. The Afib risk score (range 0-7) was defined as the sum of the scores of these independent factors. The risk of incident Afib among patients with risk scores of 0-1, 2-3, 4, and 5+ is shown in Figure 1B. Rates for these 4 groups were significantly different (p<0.001), with the 10-year Afib rates (95% C.I.) for those with a score of 0-1, 2-3, 4, and 5+: 4% (2-6%), 9% (6-13%), 17% (11-23%), and 33% (20-43%), respectively. CONCLUSIONS: A history of Afib is present in approximately 1 out of every 16 patients with newly diagnosed CLL. Among patients without Afib at diagnosis, the incidence rate of Afib is ~1%/year. The risk of incident Afib in newly diagnosed CLL patients can be predicted based on age, sex, and co-morbid health conditions present at diagnosis. These data provide context to help interpret data on the frequency of Afib in CLL patients treated with ibrutinib and other novel agents. Disclosures Shanafelt: Janssen: Research Funding; Polyphenon E Int'l: Research Funding; Glaxo-Smith_Kline: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Pharmactckucs: Research Funding. Ding:Merek: Research Funding. Kay:Tolero Pharm: Research Funding; Hospira: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Gleimer, Michael, Yumeng Li, Lawrence Chang, Sophie Paczesny, David Hanauer, David Frame, Craig A. Byersdorfer, Pavan Reddy, Thomas M. Braun, and Sung Won Choi. "Baseline Body Mass Index Among Children and Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: Clinical Characteristics and Outcomes." Blood 124, no. 21 (December 6, 2014): 2558. http://dx.doi.org/10.1182/blood.v124.21.2558.2558.
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Abstract Obesity is a serious public health problem accompanying changes in diet and physical activity. The rising prevalence of obesity may influence the outcomes of hematopoietic cell transplantation (HCT). We studied 898 children and adults receiving first-time allogeneic bone marrow or peripheral blood stem cell transplants between 2004 and 2012 at the University of Michigan. Pre-transplant body mass index (BMI) was calculated using height and weight measurements and treated as a continuous variable. Recipients were then classified as underweight, normal weight, overweight, or obese according to BMI for adults using the World Health Organization classification system, or age-adjusted BMI percentiles for children based on Center for Disease Control and Prevention charts. The study population was predominantly Caucasian, and the median age was 51 years (5 months – 73 years). The cumulative 3-year incidence of non-relapse mortality (NRM) in underweight, normal weight, overweight, and obese patients was 20%, 19%, 20%, and 33% (p=0.04) (Figure 1A). Major causes of NRM were acute and chronic graft-versus-host disease (GVHD) (Figure 1B). The corresponding incidence of relapse was 30%, 41%, 37%, and 30% (p=0.002) (Figure 1C). Three-year overall survival was 59%, 48%, 47%, and 43% (p=0.55) (Figure 1D). Multivariate analysis showed that obesity was associated with higher NRM (hazard ratio [HR] 1.43, p=0.04), and lower relapse (HR 0.65, p=0.002) (Table 1). Pre-transplant plasma levels of ST2 and TNFR1 biomarkers were significantly higher in obese than in normal weight patients (p=0.04 and p=0.05, respectively) (Table 2). The increase in NRM observed in obese patients was partially offset by lower incidence of relapse, resulting in no significant difference in overall survival. Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Figure 1. Transplant outcomes according to BMI categories. Cumulative incidence of NRM (A), chronic GVHD (B), relapse (C), and probability of overall survival (D) according to BMI groups. N = 20 underweight (UW), 290 normal weight (NW), 287 overweight (OW), 301 obese (OB). Table 1. Results of multivariate regression analysis by BMI category. NRM Acute GVHD Chronic GVHD Relapse Overall survival Hazard ratio (95% confidence intervals), p value Normal weight 1.00 1.00 1.00 1.00 1.00 Underweight 1.74 (0.76−4.01), 0.19 1.11 (0.56−2.21), 0.76 0.99 (0.46−2.12), 0.98 0.70 (0.32−1.50), 0.36 1.02 (0.54−1.95), 0.95 Overweight 0.95 (0.65−1.37), 0.77 1.03 (0.78−1.35), 0.85 1.07 (0.83−1.38), 0.60 0.79 (0.61−1.03), 0.08 0.85 (0.68−1.07), 0.17 Obese 1.43 (1.02−2.01), 0.04 1.15 (0.89−1.50), 0.29 1.21 (0.94−1.55), 0.14 0.65 (0.49−0.86), 0.002 0.93 (0.75−1.16), 0.55 Other covariates Continuous age 1.01 (1.00−1.02), 0.18 1.00 (0.99−1.00), 0.37 1.00 (0.99−1.01), 0.69 1.00 (1.00−1.01), 0.36 1.01 (1.00−1.02), 0.003 Malignancy Non−malignant 1.00 1.00 1.00 1.00 1.00 Malignant 0.37 (0.10−1.33), 0.13 1.73 (0.82−3.68), 0.15 1.29 (0.72−2.31), 0.38 26.50 (3.49−201.02), 0.002 2.05 (0.92, 4.58), 0.08 Relatedness Related 1.00 1.00 1.00 1.00 1.00 Unrelated 2.20 (1.65−2.94), <0.001 1.88 (1.50−2.35), <0.001 1.13 (0.92−1.39), 0.23 0.61 (0.48−0.77), <0.001 1.24 (1.03−1.49), 0.02 Transplant type Peripheral blood 1.00 1.00 1.00 1.00 1.00 Bone marrow 0.23 (0.09−0.58), 0.002 0.66 (0.44−0.99), 0.04 0.91 (0.61−1.36), 0.65 1.09 (0.72−1.66), 0.68 0.56 (0.38−0.82), 0.003 HLA match Matched 1.00 1.00 1.00 1.00 1.00 Mismatched 1.59 (1.16−2.22), 0.004 1.69 (1.30−2.17), <0.001 0.95 (0.73−1.25), 0.73 0.83 (0.60−1.18), 0.29 1.41 (1.12−1.79), 0.003 Conditioning Myeloablative 1.00 1.00 1.00 1.00 1.00 Reduced 1.02 (0.76−1.35), 0.91 1.19 (0.94−1.49), 0.14 1.02 (0.82−1.27), 0.82 0.90 (0.69−1.16), 0.42 0.89 (0.74−1.09), 0.24 Year of transplant 2004−2008 1.00 1.00 1.00 1.00 1.00 2009−2013 0.79 (0.60−1.05), 0.10 0.76 (0.61−0.95), 0.02 0.96 (0.79−1.17), 0.70 0.76 (0.60−0.95), 0.02 0.78 (0.65−0.94), 0.01 Table 2. Baseline levels of plasma biomarkers suppression of tumorigenicity 2 (ST2) and tumor necrosis factor receptor 1 (TNFR1) by BMI category. ST2 TNFR1 BMI category N Median concentration (IQR), pg/ml p value N Median concentration (IQR), pg/ml p value Normal weight 115 131 (0-628) − 88 2129 (1486-3232) − Underweight 7 256 (82-659) 0.51 7 1596 (1467-2971) 0.57 Overweight 115 208 (0-845) 0.22 81 2266 (1708-3725) 0.32 Obese 110 257 (0-1045) 0.04 99 2644 (1922-3395) 0.05 Disclosures No relevant conflicts of interest to declare.
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Alvarez Reguera, C., A. Herrero Morant, L. Sanchez Bilbao, D. Martínez-López, J. L. Martín-Varillas, G. Suárez Amorín, P. Setien Preciados, M. C. Mata Arnaiz, M. Á. González-Gay, and R. Blanco. "SAT0508 DIAGNOSIS OF BEHÇET’S DISEASE: COMPARISON OF TWO SETS OF CLASSIFICATION CRITERIA. APPLICATION IN 111 PATIENTS OF A WELL-DEFINED POPULATION." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1210.3–1210. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5166.
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Background:Behçet’s disease (BD) is a systemic, chronic, relapsing vasculitis with no pathognomonic diagnostic test. The most widely used classification criteria are those of the International Study Group (ISG) for BD (1). These criteria were repeatedly found to have low sensitivity. Therefore, the International Criteria for Behçet’s Disease (ICBD) were published in 2014 (2).Objectives:To compare the ISG with ICBD diagnostic criteria for BD.Methods:The study included all consecutive 111 patients diagnosed with definitive or possible BD by expert rheumatologists. They were diagnosed at a well-defined population in Northern Spain between 1980 and 2019. The ISG and ICBD diagnostic criteria for BD were applied to and compared among all patients.Results:We studied 111 patients (62 Women/49 Men), mean age 36.8±13.2 years. BD was diagnosed in 65 (58.5%) by ISGBD criteria and in 86 (77.5%) by ICBD criteria. No significant differences were observed between both criteria (p < 0.001). The overall concordance was fair (Kappa 0.3; p<0.001). Sensitivity was 58.6% for ICBD criteria and 80.2% for ISG.(TABLE-1)Conclusion:ICBD criteria exhibit higher sensitivity than ISG criteria. Thus, the application of these new criteria can achieve a more correct and earlier diagnosis of BD.References:[1]Criteria for diagnosis of Behcet’s disease, International Study Group for Behçet’s Disease,The Lancet, Volume 335, Issue 8697, 1078 – 1080[2]The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria, J Eur Acad Dermatol Venereol. 2014; 28:338-47TABLE 1Expert diagnosis (N=111)ISG criteria -(N=65)ICBD criteria (N=86)Age, mean (SD)36.7 (13.2)36 (12.8)36.7 (13)Gender, men/women, N (%)49/62 (44.1/55.8)29/36 (44.6/55.4)38/48 (44.2/55.8)Oral aphthosis110 (99)65 (100)85 (100) -Recurrent (3 times/year)91 (87.2)61 (93.8)74 (86)Genital aphthosis59 (53.1)42 (64.6)56 (65.1)Skin manifestations76 (68.4)56 (86.15)71 (70.9) -Pseudofolliculitis/ Erythema nodosum51 (67.1)/ 27 (35.5)38 (58.5)/ 21 (32.3)42 (68.8)/ 22 (36.1)Ocular lesions39 (35.1)32 (49.2)39 (45.3) -Anterior/ Posterior/ Panuveitis17 (43.6);12 (30.8)/ 016 (50)/ 8(25)/ 7 (21.9)17 (45.6); 0; 12 (30.8) -Retinal vasculitis4 (10.3)1 (3.1)4 (10.6)Joint manifestations76 (68.5)43 (66.1)58 (67.4) -Arthralgias / Arthritis69 (92.8)/ 45 (60)39 (90.7)/ 24 (55.8)52 (89.6)/ 33 (56.9)Neurological manifestations20 (18)11 (16.9)16 (18.6) -Peripheral / Central11 (55)/ 14 (70)7 (63.6)/ 7 (63.6)12 (75)/ 10 (62.5)Vascular manifestations9 (8.6)7 (10.8)10 (11.6) -Arterial/ Vein thrombosis/ Phlebitis0/ 5 (55)/ 1 (11.1)0/ 4 (57.1)/ 1 (14.3)1 (12.5)/ 5 (62.5)/0Gastrointestinal features4 (4.5)4 (6.1)4 (4.6)Pathergy test positive (available data; %)6 (28; 21.4)4 (19; 21)4 (25, 16)HLA B51 positive (available data; %)38 (86; 44.2)19 (47; 40.4)28 (63; 44.4)Disclosure of Interests:Carmen Alvarez Reguera: None declared, Alba Herrero Morant: None declared, Lara Sanchez Bilbao: None declared, David Martínez-López: None declared, José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Guillermo Suárez Amorín: None declared, Patricia Setien Preciados: None declared, M. Cristina Mata Arnaiz: None declared, Miguel Á. González-Gay Grant/research support from: AbbVie, MSD and Roche, Speakers bureau: AbbVie, MSD and Roche, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD
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Biewen, Carter, Angela R. Smith, Jakub Tolar, and Weston P. Miller. "Outcomes after Donor Lymphocyte Infusion for Insufficient Donor Chimerism Following Hematopoietic Cell Transplantation for Non-Malignant Disorders." Blood 126, no. 23 (December 3, 2015): 1969. http://dx.doi.org/10.1182/blood.v126.23.1969.1969.
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Abstract Background: Little is reported of the utility of donor lymphocyte infusion (DLI) following HCT for non-malignant disorders (NMD). We describe outcomes after DLI for insufficient donor chimerism after HCT in a large NMD cohort. Patients/Methods: We queried the Institutional BMT Database for patients with NMD receiving DLI for insufficient post-HCT donor chimerism. HLA typing, graft selection and conditioning were per institutional guidelines. The use, timing and dosing of DLI was at the discretion of the treating physician. Donor chimerism values on the myeloid fraction of peripheral blood at pre-DLI and most-recent time-points were reviewed. Patients were considered best DLI responders if donor chimerism improved (pre-DLI to most-recent) and most recent chimerism was ³ 80%. Results: Twenty-three patients (43% female) were identified. Table 1 shows patient, disease, transplant and DLI characteristics. The median zenith chimerism post-HCT (but pre-DLI) was 84% (IQR, 39 - 99%), observed at a median 28 days post-HCT. The median chimerism just prior to first DLI was 40%. The median time to first DLI was 90 days. Patients underwent a median 2 cycles (IQR, 2 - 3; maximum, 5) of DLI; the median cumulative per-patient CD3+ dose was 11.5 x 106/kg. Post DLI, two patients developed aGvHD and 2 patients developed cGvHD. Five patients (22%) were best DLI responders. At a mean 3.6 years post-HCT, they retained mean chimerism of 94% (mean increase from pre-DLI of 37%). Of the 18 non-best responders (78%), median chimerism at last follow-up was 10% (IQR, 2 - 25%). Seven patients underwent repeat HCT. Best response to DLI did not depend on HCT total nucleated cell dose, donor relatedness, serotherapy agent of HCT regimen, chimerism prior to DLI, or total DLI CD3+ dose. Best responders tended to have undergone myeloablative conditioning, be HLA-matched to the donor and receive first DLI later post-HCT (median 102 days, versus 83 days). Conclusions: In a large NMD cohort undergoing DLI after HCT, sustained high donor chimerism response was observed in 22%. Ongoing analyses aim to assess those with intermediate response (many of whom also enjoy improved or stable NMD), as well as the impact of peri-DLI immune suppression on outcomes. Table 1. Patient, Disease and Transplant Characteristics. ID Dx Age (y) at HCT Conditioning/ Serotherapy Donor / Graft HCT TNC(x 108 /kg) Days# to DLI DLI@ CD3+ (x106 /kg) % Chimerism Pre/MRFU aGvHD (grade) / cGvHD Re-HCT? Survival (y#) Notes / Cause of Death 1 ALD 8.1 MA / ATG R / BM 2.16 508 6 92 / 100 n/n n A (10) SD 2 ALD 8.3 NMA / C R / BM 3.17 73 9 59 / 27 n/n n A (6) SD 3 ALD 8.4 NMA / C R / BM 3.97 51 45 44 / 23 n/n n A (4.6) SD 4 ALD 9.9 NMA / C R / BM 2.13 44 17 43 / 17 n/n n A (7.2) SD 5 HLH 18 NMA/ Unk U / BM 1.94 102 1 75 / 100 Y(4)/n n D (0.6) Viral; Resp Failure 6 HLH 1 NMA / C U / BM 9.39 181 3 3 / 4 n/n Y D (1.9) Sepsis 7 Hurler 2.5 MA / ATG R / BM 5.05 193 16 67 / 58 n/n n A (8.3) SD 8 Hurler 1 MA / C R / BM 4.25 305 1 64 / 80 n/n n A (6.7) SD 9 IPEX 1.3 NMA / Unk U / BM 4.99 160 13 44 / 56 n/n n A( 6.4) SD 10 JEB 0.5 NMA / ATG U / BM 5.22 81 6 25 / 13 n/n n D (0.4) Sepsis 11 RDEB 2.8 NMA / ATG R / BM 6.21 274 11 17 / 25 n/n n A (2.1) SD 12 RDEB 6.3 NMA / ATG R / BM 7.28 167 Unk 17 / 6 n/n n A (3.1) SD 13 RDEB 0.9 NMA / ATG U / BM 9.91 98 16 12 / 87 n/n n A (2.7) SD 14 RDEB 3.3 NMA / ATG R / BM 3.53 48 16 10 / 0 n/n Y A (1.6) SD 15 RDEB 0.9 NMA / ATG R / BM 3.35 90 65 40 / 100 n/Y n A (1) SD 16 RDEB 4.9 NMA / ATG R / BM 4.27 133 65 41 / 25 n/n n A (0.8) SD 17 RDEB 0.5 NMA / ATG R / BM 5.5 85 30 71 / 45 n/n n A (0.7) SD 18 SCD 9.1 NMA / ATG U / BM 3.19 34 0.5 0 / 0 n/n n D (13.7) Progressive SCD 19 SCD 10.2 NMA / ATG U / PBSC 0.13 57 12 69 / 4 n/n Y A (10) Rejected re-HCT 20 Thal 2.3 NMA / ATG R / BM 3 84 Unk 15 / 0 n/n Y A (7.3) E, SD 21 Thal 2.8 NMA / ATG U / PBSC 0.22 48 1 40 / 0 Y(2)/Y Y D (2.2) cGvHD 22 Thal 1.7 NMA / C U / PBSC 0.17 69 5 11 / 2 n/n Y A (7.6) E, SD 23 Thal 2.6 MA / ATG R / BM 6.23 159 Unk 17 / 4 n/n Y A (5.3) E, SD # = time referenced to HCT; @ = cumulative CD3+ cell dose; ALD = adrenoleukodystrophy; HLH = hemophagocytic lymphohistiocytosis; IPEX = immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; JEB = junctional epidermolysis bullosa; RDEB = recessive dystrophic epidermolysis bullosa; SCD = sickle cell disease; Thal = thalassemia; y = years; MA = myeloablative; NMA - non-myeloablative; ATG = anti-thymocyte globulin; C = alemtuzumab; Unk = unknown; R = related; U = unrelated; BM = marrow; PBSC = peripheral blood stem cell; TNC = total nucleated cell dose; Pre = just prior to DLI; MRFU = most recent follow-up; n = no; Y = yes; A = alive; D = dead; SD = stable disease; E = engrafted. Disclosures No relevant conflicts of interest to declare.
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Koneva, O., L. P. Ananyeva, L. Garzanova, O. Desinova, O. Ovsyannikova, and M. Starovoytova. "POS0858 POTENTIAL EFFICACY PREDICTORS OF ANTI-B-CELL THERAPY IN THE PATIENTS WITH SYSTEMIC SCLEROSIS ASSOCIATED WITH INTERSTITIAL LUNG DISEASE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 683.2–684. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2313.
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Background:Rituximab (RTM) is considered as a promising therapeutic agent for treatment of With Interstitial Lung Disease (ILD) in the patients with systemic sclerosis (SSc). However, the limited number of RTM-treated patients, considerably varying dose regimens, cumulative doses and observation periods, lack of data on potential predictors of RTM therapy response do not allow univocal conclusions on RTM efficacy or definitive recommendations on RTM use in the patients with SSc.Objectives:The study of potential efficacy predictors of anti-B-cell therapy in the patients with SSc associated with ILD.Methods:90 patients with SSc-ILD verified by multispiral computed tomography were enrolled to the study and received RTM therapy for 12-42 months at cumulative dose 2.9±1.1 grams (disease duration 5.9±4.8 years, diffused/limited SSc 1.3/1, average age 47 ± 13.6 years, females 83%). All patients received low or moderate dose glucocorticoids. 45 patients received RTM in addition to immunosuppressive therapy (cyclophosphamide and mycophenolate mofetil) because of inadequate efficacy of immunosuppressants. After evaluation of FVC trends in the patients receiving RTM the overall study population was divided into two patient groups for the analysis: group A (n=35) comprised the patients with ≥10% FVC increase (disease duration 6.1±5.8 years, diffused/limited SSc 1,3/1, average age 50±12 years, females 86%, cumulative RTM dose 3.2±1.24 grams), and group B (n=11) comprised the patients with ≥5% FVC decrease (disease duration 5.2±4, diffused/limited SSc 0.8/1, average age 43±16, females 72%, cumulative RTM dose 2.5±0.99 grams). Subsequently correlation analysis was made to clarify the association between delta FVC and a number of clinical (age, gender, duration and form of SSc, modified skin count, presence of gastroesophageal reflux, mPAP, SSc activity (EScSG, points), cumulative RTM dose, immunosuppressive therapy) and laboratory parameters (ESR, ANA-НЕР-2, a-Scl-70, CRP, B cell count).Results:In the overall patient population RTM therapy was associated with significant FVC increase from 77.0±19.9 % to 84.7±20.9% (р=0.000000), with median FVC increment 6.6% [0;14.1].In group A FVC increased from 75.3±19.9 to 94.3±20.4) (р=0.000000), with median FVC increment 16.3 [12.6; 24.7].In group B FVC decreased from 82.5 ±23.2 to 72,3±19.4 (р=0,000176), with median FVC decrement 10.4% [-13.4; -6].Correlation analysis in groups A and B showed significant association of between delta FVC and the patient age (R=0.36), cumulative RTM dose (R=0.34) and EScSG during the last examination (1.2±.,0 and 3.1±1.4 in groups A and B, respectively; R=-0.42).No significant correlation between delta FVC and any other tested parameters was found.Conclusion:Therefore, older patients who received the cumulative rituximab dose more than 3 grams with suppressed SSc activity achieved greater FVC increase at the background of therapy. These data allow to consider the above parameters as potential predictors of response to anti-B-cell therapy in the patients with SSc-ILD.Disclosure of Interests:None declared
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Yu, Yao, Heiko Schöder, Jung Kang, Sean Matthew McBride, C. Jillian Tsai, Linda Chen, Kaveh Zakeri, et al. "Postoperative PET/CT for detection of early recurrence (ER) after surgery for squamous cell carcinomas (SCC) of the oral cavity (OC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 6060. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.6060.
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6060 Background: Patients with ER after surgery and prior to postoperative radiation (RT) for SCC of the OC have aggressive biology and poor prognosis. After the introduction of a PET/CT simulator in our department, we incorporated post-operative PET/CT as part of RT planning. We hypothesized PET/CT would improve detection of macroscopic disease before postoperative RT. Methods: We reviewed the medical records of patients treated with postoperative radiotherapy between 2005 and 2019 for OC SCC. Clinicopathologic risk factors were recorded. Intermediate risk factors (IRFs) included pT3-4 disease, nodal disease, perineural invasion (PNI), lymphovascular invasion (LVI), and close ( < 5mm) surgical margins (SM); extranodal extension (ENE) and positive SM were considered high-risk factors (HRF). Patients were stratified into risk groups based upon the number and type of risk factors: 0-1 IRFs, 2 IRFs, ≥3 IRFs, and any HRF. Patients were considered to have ER if they had biopsy confirmed recurrence, or if the imaging or exam was sufficiently suspicious, after discussion with the head and neck team, to warrant treatment to definitive doses of RT (70 Gy). Results: Our cohort included 391 patients with SCC of the OCC who were treated with postoperative radiotherapy. 61% of patients were male, 35% had pT3-4 disease, 36% had pN2a-3 disease, 53% had PNI, 20% had LVI, 30% had ENE, and 14% had positive SM. The most common sites were oral tongue (46%), alveolar ridge (18%), and buccal mucosa (13%). 237 (61%) patients underwent postoperative PET/CT planning, and 165 patients (41%) were planned with CT only. Patients screened with post-operative PET/CT were more likely to be diagnosed with ER (46/237, 19.4%) than those simulated with CT only (6/154, 3.9%, p < 0.0001). Among patients simulated with PET/CT, 7%, 9%, 14%, and 35% of patients were diagnosed with ER for patients with 0-1 IRFs, 2 IRFs, ≥3 IRFs, and any HRF, respectively. Median follow-up was 4.1 years (95% CI 3.6 – 4.5). Among 52 patients with ER, 24 (49.0%) had local, 41 (83.7%) had regional, and 5 (10.2%) had distant recurrence. 17 (33%) of ER were biopsy proven. For patients with ER, 3-year freedom from locoregional recurrence, distant-metastasis free survival, and overall survival were 45.2% (95% CI 32% - 64%), 55% (95% CI 42% – 72%), and 43% (95% CI 30% - 61%), respectively. For patients without ER, use of postoperative PET/CT was associated with improved disease-free survival (HR 0.68, 95% CI 0.46 – 0.98, p = 0.041) and overall survival (HR 0.59, 95% CI 0.38 – 0.91, p = 0.019). Conclusions: Postoperative PET/CT may increase detection ER compared to CT simulation alone and improve risk stratification. Patients with ER are at high risk of locoregional failure, distant metastases, and mortality, despite salvage therapy. A prospective trial is underway at our institution to systemically study the role of PET/CT for detection of ER.
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Rodeghiero, Francesco, Andrew Provan, Michael Steurer, Bertrand Godeau, Nancy Carpenter, and Georg Kreuzbauer. "Pooled Analysis of Safety and Efficacy of Romiplostim in Splenectomized and Nonsplenectomized Patients (pts) with Immune Thrombocytopenia (ITP)." Blood 124, no. 21 (December 6, 2014): 4199. http://dx.doi.org/10.1182/blood.v124.21.4199.4199.
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Abstract Introduction: Romiplostim is a thrombopoietin receptor agonist approved for use in adult pts with ITP. Pooled analyses of combined pt data from romiplostim ITP clinical studies have previously been reported. Here we report updated safety and efficacy data according to baseline splenectomy status. Methods: Data from adult pts in 13 completed ITP studies with romiplostim were analysed up to June 2014. Pts received romiplostim, placebo or medical standard of care (SOC) and data from the placebo/SOC arms were pooled. All 13 studies were included in analyses of baseline pt characteristics and safety endpoints; 4 early dose-finding studies were excluded from analyses of efficacy endpoints as they do not reflect the current dosing of romiplostim. Adverse events were adjusted for time spent on study and reported as rates per 100 pt-years. For pts who started their parent study in the placebo/SOC group and then went on to receive romiplostim in an extension study, all data from the first dose of romiplostim were included in the romiplostim group. A platelet response was defined as a platelet count ≥50x109/L without rescue medication in the previous 8 weeks; a platelet response for 9 out of any 12 consecutive weeks on-study was considered a sustained platelet response. All analyses were descriptive and no statistical testing was performed. Results: Data from 1,111 pts were analysed, 395 splenectomized and 716 nonsplenectomized. The splenectomized and nonsplenectomized groups were similar in age (median 52 vs 53 years) and sex (female 64% vs 60%), but in the splenectomized group median baseline platelet counts were slightly lower (14 vs 19x109/L) and a higher proportion of pts were known to have received >3 prior ITP treatments (38% vs 12%) than the nonsplenectomized group. Rates of AEs, serious AEs, fatal AEs, treatment-related AEs, thrombotic events, and hemorrhages were lower in nonsplenectomized than splenectomized pts and were in general lower in romiplostim than placebo/SOC-treated pts in both groups. Bone marrow reticulin occurred in 17 romiplostim-treated pts and one placebo-treated pt, at a slightly increased rate in splenectomized vs nonsplenectomized pts. Bone marrow collagen was reported in one romiplostim-treated nonsplenectomised pt. Data from 1,024 pts were analysed for efficacy (376 splenectomized, 648 nonsplenectomized). The median (Q1, Q3) most frequent weekly dose was 4 µg/kg (2, 9) in splenectomized and 3 µg/kg (2, 7) in nonsplenectomized pts. A platelet response was achieved in 82% of splenectomized and 91% of nonsplenectomized pts and a sustained platelet response in 66% and 79%, respectively. The median time to first response was 2.1 weeks for splenectomized and 2.0 weeks for nonsplenectomized pts. Platelet responses were maintained in those who responded: after the first response the median (Q1, Q3) proportion of time with a response was 97% (79%, 100%) for splenectomized and 100% (91%, 100%) for nonsplenectomized pts. Conclusions: A relatively large number of nonsplenectomized pts have received romiplostim in clinical studies. Safety of romiplostim was comparable in splenectomized and nonsplenectomized patients with no new safety signals observed, and platelet response rates were high and of sustained duration in both groups. Abstract 4199. Table Number of events (rate per 100 pt-years) Splenectomized Nonsplenectomized Placebo/SOC N=27 Pt-yr=11.2 Romiplostim N=391 Pt-yr=702.0 Placebo/SOC N=106 Pt-yr=97.7 Romiplostim N=655 Pt-yr=1129.7 All AE 208 (1861.1) 8609 (1226.3) 1028 (1052.6) 9624 (851.9) Serious AE 15 (134.2) 478 (68.1) 92 (94.2) 498 (44.1) Fatal AE 3 (26.8) 11 (1.6) 5 (5.1) 31 (2.7) Treatment-related AE 15 (134.2) 864 (123.1) 152 (155.6) 928 (82.1) Treatment-related serious AE 0 (0) 65 (9.3) 18 (18.4) 59 (5.2) Treatment-related fatal AE 0 (0) 2 (0.3) 0 (0) 3 (0.3) Thrombotic events 1 (8.9) 44 (6.3) 5 (5.1) 52 (4.6) Hemorrhage events 54 (483.2) 1868 (266.1) 233 (238.6) 1591 (140.8) Fatal hemorrhage events 1 (3.7) 0 (0) 0 (0) 5 (0.8) Bone marrow reticulin /collagen events* 1 (8.9) 11 (2.0) 0 (0) 7 (0.8) Hematologic malignancies/MDS 0 (0) 6 (0.9) 4 (4.1) 8 (0.7) Any malignancies 0 (0) 24 (3.4) 9 (9.2) 43 (3.8) * Bone marrow collagen reported in one romiplostim-treated nonsplenectomized pt. Excludes study NCT00907478 as bone marrow evaluations were collected differently than in other studies; in the romiplostim arms the N/pt-yrs were 331/560.6 for splenectomised and 546/866.7 for nonsplenectomised pts. Disclosures Rodeghiero: GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Suppremol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Steurer:Amgen: Honoraria. Godeau:Amgen: Consultancy. Carpenter:Amgen: Employment, Equity Ownership. Kreuzbauer:Amgen: Employment, Equity Ownership.
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Horwitz, Steven M., James M. Foran, Michael Maris, Jennifer Kimberly Lue, Ahmed Sawas, Craig Okada, Tatyana A. Feldman, et al. "Updates from Ongoing, First-in-Human Phase 1 Dose Escalation and Expansion Study of TTI-621, a Novel Biologic Targeting CD47, in Patients with Relapsed or Refractory Hematologic Malignancies." Blood 138, Supplement 1 (November 5, 2021): 2448. http://dx.doi.org/10.1182/blood-2021-154490.
Full textAbstract:
Abstract Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "don't eat me" signal to suppress macrophage phagocytosis. Overexpression of CD47 can allow tumor cells to escape immune surveillance. TTI-621 (SIRPαFc) is a fusion protein consisting of the CD47 binding domain of human SIRPα linked to the Fc region of human IgG1, designed to enhance phagocytosis and antitumor activity by blocking the CD47-SIRPα interaction between malignant cells and macrophages, and engaging Fcγ receptors. Here we report updates from the dose optimization part of the first-in-human study of TTI-621 (NCT02663518), testing dose levels between 0.5-2.0 mg/kg in patients with cutaneous T-cell lymphoma (CTCL). Methods This study has been conducted in 4 parts. Part 1 tested increasing weekly intravenous doses of TTI-621 based on 3+3 escalation. The maximum tolerated dose was initially determined to be 0.2 mg/kg based on dose limiting toxicity (DLT) of thrombocytopenia [defined as Grade (Gr) 4 of any duration]. Expanded testing followed in patients with hematologic malignancies. In Part 2, most patients received 0.2 mg/kg; however, based on investigator discretion, a subset of patients received escalating doses up to 0.5 mg/kg. In Part 3, patients with T-cell lymphomas received stepwise dose escalations from 0.2 to 0.5 mg/kg over the first 5−8 weeks. Part 4 (dose optimization) of this study, is currently ongoing with weekly TTI-621 treatment escalating in a standard 3+3 manner through 5 planned dose levels including 0.5, 0.7, 1, 1.4, and 2 mg/kg. Dose optimization is being assessed in patients with CTCL. The DLT criteria was modified to require Gr 4 thrombocytopenia lasting >72 hours. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) per CTCAE v 4.03. Blood samples are obtained for pharmacokinetics and disease assessments are performed per Olsen's criteria. Results In Parts 1−3 (n=214), the most common related AEs were infusion-related reaction (IRR, 43%; 3% Gr ≥3), thrombocytopenia (30%; 22% Gr ≥3), chills (22%; 0% Gr ≥3), and fatigue (16%; 1% Gr ≥3). Objective responses to single agent TTI-621 were achieved in 14/71 (20%) NHL pts including CTCL (n=42, 1 CR, 7 PRs), PTCL (n=22, 2 CRs, 2 PRs) and DLBCL (n=7, 1 CR, 1 PR). In Part 4 as of April 12, 2021, 24 patients (17M/7F, median age 65 years) have enrolled into the 5 dose cohorts including 9 patients in the 2.0 mg/kg dose level. CTCL subtypes enrolled include mycosis fungoides (MF, n=18) and Sézary syndrome (SS, n=6). Disease stage was advanced (≥IIB) in 16 (67%) patients and a median of 3 (range 1−12) prior systemic therapies were received. Related AEs occurred in 19 (79%; 33% Gr ≥3) patients including infusion-related reaction (IRR, 50%; 13% Gr ≥3), thrombocytopenia (33%; 25% Gr ≥3), and neutropenia and headache, (13%, 0% Gr ≥3, each). Thrombocytopenia generally occurred on dosing days, and typically recovered within 2-4 days. A total of 15 IRRs have occurred in 12 (50%) patients at all doses levels. Most IRRs occurred during initial infusions only and typically resolved within the day of occurrence. The occurrence of Gr 3 IRRs prompted the addition of corticosteroids to the pre-medication regimen which largely prevent their occurrence. Aside from IRRs and thrombocytopenia which was manageable, AEs were predominantly Gr ≤2. Pharmacokinetic results reveal continued dose-dependent increases in exposure. Objective responses have been observed in 4 of 20 (20%) evaluable patients to date, including 3 partial responses in 14 patients with MF and 1 complete response in 6 patients with SS. Treatment is ongoing in the patient who achieved CR (10+ months) and in 2 of 3 patients who achieved PR (3 and 4 months). A third patient who achieved PR elected to discontinue study treatment at 5 months to pursue allogeneic stem and progenitor cell transplantation. Conclusions Preliminary results from dose optimization testing indicate that weekly infusions of TTI-621 up to 2 mg/kg are generally well tolerated. In Part 4, an overall response rate of 20% has been observed thus far in patients with CTCL. Testing of TTI-621 in alternative dosing schedules is in progress. With demonstrated good tolerability and robust single agent antitumor activity in heavily pre-treated patients, additional testing of TTI-621 beyond relapsed/refractory lymphoma has started. Disclosures Horwitz: Affimed: Research Funding; ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Aileron: Research Funding; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. Foran: pfizer: Honoraria; novartis: Honoraria; servier: Honoraria; bms: Honoraria; revolution medicine: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; gamida: Honoraria; OncLive: Honoraria; abbvie: Research Funding; boehringer ingelheim: Research Funding; takeda: Research Funding; trillium: Research Funding; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Lue: Epizyme: Consultancy; TG Therapeutics: Consultancy; Kymera Therapeutics: Research Funding; AstraZeneca: Speakers Bureau; Kura Oncology: Consultancy. Sawas: Affimed: Research Funding; Roche: Current equity holder in publicly-traded company; Flat Iron Health: Current Employment; Seattle Genetics: Honoraria; Acrotech: Honoraria; Daiichi-Sankyo: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Sokol: Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Dren Bio: Membership on an entity's Board of Directors or advisory committees. Mei: Janssen: Honoraria; EUSA: Honoraria; TG Therapeutics: Research Funding; Epizyme: Research Funding; BMS: Research Funding; Morphosys: Research Funding; Beigene: Research Funding. Flinn: AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Villa: Janssen: Honoraria; Roche: Honoraria; Lundbeck: Honoraria; Celgene: Honoraria; Seattle Genetics: Honoraria; AbbVie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria; NanoString Technologies: Honoraria. Percival: Pfizer: Research Funding; Abbvie: Research Funding; Biosight: Research Funding; BMS/Celgene: Research Funding; Cardiff Oncology: Research Funding; Glycomimetics: Research Funding; Nohla Therapeutics: Research Funding; Oscotec: Research Funding; Trillium: Research Funding. Savage: Seattle Genetics: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Roche: Research Funding; Takeda: Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Diefenbach: Genentech, Inc./ F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; MEI: Consultancy, Research Funding; Gilead: Current equity holder in publicly-traded company; IMab: Research Funding; Celgene: Research Funding; Trillium: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Perlmutter Cancer Center at NYU Langone Health: Current Employment; IGM Biosciences: Research Funding. Kim: Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Corvus: Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Galderma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elorac: Research Funding; Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding; Soligenix: Research Funding; Eisai: Research Funding; CRISPR: Research Funding; Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Secura Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion, AstraZeneca Rare Disease: Other: Study investigator; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Horizon: Research Funding. Lin: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Catalano: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Petrova: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Uger: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Molloy: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Large: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Bruns: Trillium Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.
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Pavlovsky, Santiago, Claudia S. Corrado, Miguel A. Pavlovsky, Mario Giunta, Lucia Zoppegno, Virginia Prates, Francisco Lastiri, et al. "Risk-Adapted Therapy in Adults Previously Untreated Hodgkin’s Lymphoma (HL) with ABVD Followed by Involved Field Radiotherapy (IFRT)." Blood 104, no. 11 (November 16, 2004): 1310. http://dx.doi.org/10.1182/blood.v104.11.1310.1310.
Full textAbstract:
Abstract Background: The present goal for the treatment of HL is to develop a combined modality therapy with high response rate, disease-free survival (DFS) and overall survival (OSV) with minimal toxicity. Methods: On December 1996, the GATLA started a non randomized protocol for 15 to 75 years old (median 28) patients previously untreated. Patients with clinical stage I, II, IIIA without bulky tumor (< 10 cm mass or < 1/3 thoraxic diameter) (low risk) received 3 cycles of ABVD followed by IFRT 25 Gy to all node areas of more than 2 cm at diagnosis. A total of 46 out of 218 patients (21%) with low risk who failed to achieve complete remission (CR) after 3 cycles of ABVD were included as high risk completing 6 cycles of ABVD. Patients with clinical stage IIIB and IV or all other stages with bulky disease or persistance lymph nodes areas after 3rd cycle of ABVD (high risk) received 6 cycles of ABVD followed by IFRT 30 Gy to residual areas after the third cycle of ABVD or bulky areas at diagnosis. The dose of ABVD was the standard; Adriamycin 25 mg/m2, Bleomycin 10 IU/m2, Vinblastine 6 mg/m2 and Dacarbacine 375 mg/m2 all IV on day 1 and 15 of each 28 days cycles. Patients who achieved partial remission (PR) were salvage with other regimen mainly ESHAP x 3 cycles followed by high dose therapy with autograft rescue. Results: A total of 171 (99%) out of 172 patients with low risk achieved CR. One 74 year old patient died of pneumonia after the third ABVD. A total of 187 (85%) of 219 patients with high-risk achieved CR, 25 PR, and 7 failed to respond (FR) (P<0,001). The estimate DFS at 60 months was 92% and 67% (P< 0.001), while the OS was 98% and 89% (P=0.004) for low and high risk respectivelly. Of the 25 patients with PR, all received second line therapy followed in 15 by an autograft. Twelve patients are in CR, 5 are in PR, 2 in progressive disease and 6 died. Of the seven who FR, four died of PD an three are alive with the disease. One patient developed a MDS/AML after relapsing from an autograft and 8 months after having been rescued with BEACOPP. Five other second cancer (1 ovary, 2 NHL, 1 lung, 1 colon) appeared after treatment, two died and 3 remain in CR of their HL. Using the IPI HL 165 patients (48%) have scored 0–1, 145 (43%) scored 2–3, and 30 (9%) scored 3–4. The rate of CR was 96%, 88% and 87% respectively (P<0.016). The EFS at 60 months was 89%, 72% and 55% respectively (P=0.004). The OSV was 98%, 89% and 86% (P=0.037). Conclusions: We can conclude by saying that with risk-adapted therapy, 92% of the 391 patients achieved CR, with a CR + PR response of 98%. A total of 78% are event-free and 93% are alive at 60 months with remarkable low-toxicity.
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Yang, Mindy M., Mary Ann, Dawn E. Riordan, Min Fu, Victor Moyo, and Richard C. Woodman. "Iron Deficiency Is Common in Anemic Elderly Patients: Results with sTfr Index." Blood 106, no. 11 (November 16, 2005): 3763. http://dx.doi.org/10.1182/blood.v106.11.3763.3763.
Full textAbstract:
Abstract Chronic anemia is common in the elderly (≥65) with a prevalence often exceeding 10%. Multiple comorbidities and multiple causes of anemia complicate anemia diagnosis in the elderly. Iron deficiency anemia (IDA) and anemia of chronic inflammation (ACI) both commonly occur in the elderly. Distinguishing ACI from the combination of IDA and ACI is difficult with conventional tests (serum iron, TIBC, TSAT, and ferritin), especially in elderly patients or those with multiple comorbidities. Recently, the serum transferrin receptor (sTfr) has been recommended to assess iron stores, although there is limited data in the elderly. Unlike ferritin, TIBC, or TSAT, sTfr Index (sTfr(mg/L)/[log10ferritin]) is not influenced by pro-inflammatory cytokines and may provide a more precise classification of iron status. Purpose: To determine the occurrence of iron deficiency alone or in combination with ACI in the elderly using the sTfr Index. Methods: The results of the sTfr Index were compared to ferritin, as well as serum iron, TIBC, and TSAT to determine the presence of iron deficiency alone or in combination with ACI. An sTfr Index of ≥2.0 was used to define iron deficiency. Data were obtained from ambulatory, community-dwelling elderly screened for three clinical trials for treatment of chronic anemia (Hb≤11g/dL x >3 months) using epoetin alfa. No patients had a history of GI bleeding, active cancer, or recent infections. At the time of evaluation, no patients were receiving iron therapy. GFR was calculated using the Modification of Diet for Renal Disease (MDRD) Equation. Results: A total of 81 patients (mean age 75±6, range 66–89 years; 68 women and 13 men) were studied. Of these patients, 43 patients had a history of rheumatoid arthritis. 32% were African-American, 64% Caucasian, and 4% Hispanic/American-Indian. For the entire cohort, mean Hb was 10.3±0.9 g/dL; ferritin 148.0±180.9ng/mL; iron 61±33mcg/mL; TIBC 311±69mcg/dL (n=80); TSAT 19.7±11.0%; GFR 59.2±28.0mL/min/1.73m2 (n=78); sTfr Index was 3.02±3.16. There was no statistically significant difference in the severity of anemia between patients with and without iron deficiency (sTfr Index ≥2.0, Hb 10.3±0.8 vs. sTfr Index <2.0, Hb 10.4±1.0g/dL). The following table summarizes the distribution of sTfr Index stratified by ferritin concentration. Twenty-six of 35 (74%) patients with a ferritin 30–100 ng/mL had sTfr Index ≥2.0 consistent with iron deficiency. However, using conventional iron tests (meeting 2 of 3 criteria: TIBC >450mcg/dL, iron <60mcg/dL, TSAT <15%), only 19 of the 26 patients would have been identified as having IDA. Surprisingly, 9 of 33 (27%) patients with ferritin >100ng/mL also had sTfr Index ≥2.0 suggesting functional iron deficiency in combination with ACI. Among all patients included in this analysis, compared to conventional iron tests, an univariate logistic regression analysis showed that with each unit increase in sTfr Index, the odds of being iron deficient, identified by conventional tests, significantly increased 3.4-fold (p<0.0001, 95% CI: 1.8–6.1). Conclusions: Results with the sTfr Index suggest that iron deficiency in the elderly may be more common than reported with conventional iron tests. In community-dwelling elderly patients with ferritin levels consistent with ACI (>100ng/mL) may have concomitant functional iron deficiency. The use of sTfr in older adults with milder anemia (Hb>11g/dL) should also be evaluated. Ferritin (ng/mL) sTfr Index < 30 30–100 > 100 < 2.0 0 9 24 2.0 – 3.0 1 17 5 >3.0 12 9 4 Total 13 35 33
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Saleh, Mansoor N., Gregory Cheng, James B. Bussel, Paul Burgess, Lisa Marcello, Christine K. Bailey, and Andres Brainsky. "Safety and Efficacy of Extended Treatment with Eltrombopag in Adults with Chronic Immune Thrombocytopenia (ITP) From June 2006 to February 2011,." Blood 118, no. 21 (November 18, 2011): 3296. http://dx.doi.org/10.1182/blood.v118.21.3296.3296.
Full textAbstract:
Abstract Abstract 3296 Background: Eltrombopag is an oral, nonpeptide thrombopoietin receptor agonist approved for treatment of chronic immune thrombocytopenia (ITP). In 6-week, and 6-month, placebo-controlled trials, eltrombopag safely increased platelets and reduced bleeding in patients (pts) with previously treated chronic ITP. EXTEND is an ongoing, open-label extension study of the safety and efficacy of long-term treatment with eltrombopag in chronic ITP pts. Methods: Pts had received eltrombopag or placebo in one of the following studies: TRA100773A or B (6-weeks), RAISE (6-months), or REPEAT (intermittent treatment). The EXTEND study was designed to: 1) identify an individual dose that increases platelets to ≥100,000/μL to support reduction of concomitant ITP medications, 2) identify a minimal dose of eltrombopag and concomitant ITP medication to maintain platelets ≥50,000/μL, and 3) evaluate long-term safety and efficacy. Pts completed the study if they completed ≥2 years of therapy and transitioned off study due to commercial availability of eltrombopag. Results: Of 301 pts enrolled, 21% (63) completed the study, 48% (143) withdrew, and 32% (95) remain on study. The most common reasons for withdrawal were adverse events (AEs, 14%), pt decision (13%), and lack of efficacy (11%). At baseline, platelet counts were ≤15,000/μL, >15,000-<30,000/μL, 30,000–50,000/μL, and >50,000/μL in 43%, 27%, 17%, and 13% of pts, respectively; 38% were splenectomized, 34% were receiving concomitant ITP medication, and 53% had received ≥3 previous ITP therapies. As of this report, 252, 215, 176, and 84 pts had been treated for ≥6 months, 1 year, 2 years, and 3 years, respectively. Twenty-three pts (8%) were treated for ≥4 years. Median duration of exposure was 121 weeks (range, 0.3–237 weeks). Overall, 88% (264/301) of pts achieved a platelet count ≥50,000/μL at least once. The proportion of pts achieving on-treatment platelets ≥50,000/μL was similar regardless of the following baseline characteristics: splenectomy vs no splenectomy (85% vs 89%); use vs no use of ITP medication (89% vs 87%); and platelet counts (<30,000/μL, 84%; 30,000–50,000/μL, 98%; >50,000/μL, 95%). Median platelet counts increased to ≥50,000/μL by week 2 and remained consistently ≥50,000/μL through week 208. The incidence of any bleeding symptoms (WHO grades 1–4) decreased from 56% at baseline to 16%, 19%, and 9% at weeks 52, 104, and 156, respectively. Clinically significant bleeding (WHO grades 2–4) decreased from 16% at baseline to 3%, 5%, and 0% at weeks 52, 104, and 156, respectively. AEs and serious AEs (SAEs) occurred in 89% (269) and 29% (86) of pts, respectively. The most frequent AEs were headache (27%), nasopharyngitis (24%), and upper respiratory tract infection (21%). Forty pts (13%) had AEs leading to withdrawal; 28 (9%) had SAEs leading to withdrawal. Twenty-five thromboembolic events (TEEs) have been reported in 19 pts (6%); the incidence rate is 3.02/100 pt years (95% CI [1.82–4.71]). Observed TEEs were deep vein thrombosis (10), central nervous system ischemic events (7), myocardial infarction (5), and pulmonary embolism (3). No association has been observed with elevated platelet counts, as only 3/19 pts experienced the TEE at or closest to their maximum platelet count achieved on study. Hepatobiliary laboratory abnormalities (HBLAs) meeting drug-induced liver injury screening criteria (Center for Drug Evaluation and Research 2009 [FDA]) were reported in 34 pts (11%). None were associated with signs of liver impairment, and most (n=30) resolved either while on treatment or after discontinuation. Eight pts were withdrawn as a result of their HBLA. Two pts were diagnosed with lymphoma and none with leukemia during the 622 pt years of eltrombopag exposure during EXTEND. An independent central review of bone marrow biopsies from >100 pts treated with eltrombopag for 1–4 years, including 39 pts who had ≥2 biopsies during the study, revealed no clinically significant increase in reticulin deposition. Conclusions: Eltrombopag was effective in increasing and maintaining platelet counts ≥50,000/μL and reducing bleeding symptoms. Eltrombopag was well-tolerated during treatment of pts with chronic ITP with exposures up to 4.5 years. No new safety signals have been observed in this long-term study. Additional long-term safety data continue to be assessed, especially in terms of bone marrow reticulin, HBLAs, and TEEs. Disclosures: Saleh: GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau. Cheng:GlaxoSmithKline: Speakers Bureau. Bussel:Portola: Consultancy; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cangene: Research Funding; Genzyme: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sysmex: Research Funding. Burgess:GlaxoSmithKline: Employment, Equity Ownership. Marcello:GlaxoSmithKline: Employment. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership.
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Harris, Andrew C., Jaap Jan Boelens, Kwang Woo Ahn, Mingwei Fei, Allistair Abraham, Andrew Artz, Christopher C. Dvorak, et al. "Comparison of Outcomes for Myeloablative Conditioning Regimens Combining Busulfan with Either Cyclophosphamide or Fludarabine in Children." Blood 128, no. 22 (December 2, 2016): 664. http://dx.doi.org/10.1182/blood.v128.22.664.664.
Full textAbstract:
Abstract Myeloablative busulfan with cyclophosphamide (BuCy) has been the standard conditioning regimen for children with myeloid malignancies and certain non-malignant conditions. While effective, this regimen has historically high rates of regimen-related toxicities such as sinusoidal obstruction syndrome (SOS; 20-50%) and hemorrhagic cystitis (5%-15%). Substituting fludarabine for cyclophosphamide (BuFlu) has led to less toxicity and better outcomes in adult patients, prompting many pediatric centers to adopt this regimen despite sparse pediatric medical literature. We utilized the CIBMTR database to compare toxicity and outcomes of BuCy and BuFlu in pediatric patients. Methods: We identified 1781 patients aged 0-18 receiving a first allogeneic transplant with myeloablative BuCy (N=1400) or BuFlu (N=381) from 2008-2014. We excluded recipients of cord blood, T-cell depleted grafts and haplo-identical donors. The completeness index of follow up was 93% at 2 years. Transplant-related mortality (TRM), relapse and disease free survival (DFS) for patients with malignant diseases, and overall survival (OS) for all patients were compared between regimens. For a subset of patients with available comprehensive reporting (N=528; BuCy N=364, BuFlu N=164), we compared neutrophil and platelet engraftment, SOS, non-infectious hemorrhagic cystitis and pulmonary toxicity, graft failure, infections, acute and chronic GVHD between regimens. Results: For patients with non-malignant diseases (BuCy N=627, BuFlu N=176; Table 1), the BuFlu group had a higher proportion of patients with HCT-comorbidity index (HCT-CI) ≥3 and unrelated donors with single HLA-antigen mismatches. With BuCy, SOS and hemorrhagic cystitis occurred at historical rates and more frequently than BuFlu (16% vs. 7%, p=0.04, and 9% vs. 2%, p=0.04). BuFlu recipients experienced better platelet engraftment by day 28 (40% vs. 59%, p=0.005). There was no difference in graft failure, neutrophil engraftment, infections or GVHD (all p>0.05). There was no difference in 2-yr OS (p=0.8). On multivariate analysis, conditioning regimen had no impact on survival (p=0.5). For patients with malignant diseases (BuCy N=773; BuFlu N=205; Table 1), the BuFlu group had a higher proportion of patients with HCT CI ≥ 3, unrelated donors with single HLA-antigen mismatches, more frequent use of peripheral blood stem cells (PBSC) and ATG. BuFlu was associated with better day 28 neutrophil (91% vs 94%, p=0.002) and platelet engraftment (43% vs 67%, p<0.001), but no differences in engraftment at day 100. There were no differences in SOS (15% vs 13%, p=0.66), hemorrhagic cystitis, (8% vs 7%, p=0.75) pulmonary toxicity, infections and GVHD between regimens. Univariate analysis demonstrated inferior 2-year DFS (62% vs. 56%, p=0.03) and OS (71% vs. 61%, p=0.001) with BuFlu, but no significant differences in TRM or relapse. Multivariate analysis including only risk factors that were significant on multivariate analysis demonstrated higher mortality attributable to BuFlu (HR 1.4, p<0.008; Table 2), but not DFS. The most common indication for busulfan-based conditioning in children is acute myeloid leukemia (AML) in complete remission (CR). When analyzing the subset of patients with AML in CR (BuCy N=462, BuFlu N=118), there was no difference in SOS, hemorrhagic cystitis, pulmonary toxicity, acute or chronic GVHD, TRM, relapse, DFS or OS. Conclusions: The use of BuFlu in lieu of BuCy leads to faster engraftment and appeared to reduce the incidence of SOS and non-infectious hemorrhagic cystitis in patients with non-malignant diseases. Other outcomes appear comparable between regimens for patients transplanted for non-malignant diseases. Patients receiving BuFlu for malignancy experienced worse overall survival. These differences in survival were not evident for patients with AML in CR, although numbers were lower. BuFlu recipients were in general more infirm, received alternative donor grafts, PBSC or ATG more often, reflecting that the selection of conditioning was linked to specific transplant scenarios. Despite adjusting for known factors, isolating the sole impact of conditioning on survival is difficult. These findings require confirmation on prospective, randomized trials. Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding.