Journal articles: '373.21 (73) + 373.21 (71)'

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Mukherjee, Somnath, Chris Hurt, Catrin Cox, Ganesh Radhakrishna, Sarah Gwynne, Andrew Rea Bateman, Simon Gollins, et al. "Induction oxaliplatin capecitabine followed by switch to carboplatin-paclitaxel based RT versus continuing oxaliplatin capecitabine RT in operable esophageal adenocarcinoma: Survival analysis of the randomized phase II neoscope trial." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 373. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.373.

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373 Background: Initial results of the NEOSCOPE trial comparing pre-operative CarPac vs OxCap based chemoradiotherapy (CRT) in patients with adenocarcinoma of the oesophagus or oesophagogastric junction showed comparable toxicity and improvement in pathological complete response (pCR) in favour of the CarPacRT. Here we report survival after a median follow-up of 40.7 months (95% CI: 45.1-53.6). Methods: NEOSCOPE was an open, randomised, ‘pick a winner’ phase II trial. Patients with resectable oesophageal adenocarcinoma ≥ cT3 and/or ≥ cN1 were randomised to OxCapRT (oxaliplatin 85 mg/m2 day 1, 15, 29; capecitabine 625 mg/m2 bd on days of RT) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 day 1, 8, 15, 22, 29). RT dose was 45 Gy/25 fractions/5 weeks. Induction OxCap (2 cycles) was given prior to CRT. Surgery was performed 6–8 weeks after CRT.The primary endpoint was pCR, secondary endpoints were toxicity, PFS and OS. Results: Between Oct 2013 and Feb 2015, 85 patients were recruited from 17 UK centres. Median OS was not reached in the CarPacRT group and was 41.72 months (95% CI 19.58-.)in the OxCap group (HR 0.56[95% CI 0.29-1.07]; p=0.079). 3-year and 5-year OS rates were 74% (95% CI 58%-85%) and 54% (95% CI 34%-71%) (CarPacRT), and 52% (95% CI 35%-67%) and 39% (95% CI 21%-56%) (OxCapRT). Median PFS (not reached vs 35.3 months, HR=0.61 [95% CI 0.33-1.12]; p=0.111) and metastatic PFS (not reached vs 39.0 months, HR=0.61 [95% CI 0.32-1.14], p=0.118) both favoured the CarPacRT arm. Local recurrence rate was low (OxCapRT= 10%; CarPacRT= 7%). The OS benefit for CarPacRT was consistent across subgroups but not statistically significant. Conclusions: In this longer term analysis there was some evidence that induction OxCap followed by switch to CarPacRT was superior to continuing OxCapRT, with efficacy similar to that seen in other published studies such as ‘CROSS’ and ‘FLOT’. Taken together with the previously published pCR results CarPacRT rather than OxCapRT warrants inclusion in future trials. Funding: Cancer Research UK (C44694/A14614). Clinical trial information: NCT01843829.

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Crump, John A., Katrina Kretsinger, Kathryn Gay, R. Michael Hoekstra, Duc J. Vugia, Sharon Hurd, Susan D. Segler, et al. "Clinical Response and Outcome of Infection with Salmonella enterica Serotype Typhi with Decreased Susceptibility to Fluoroquinolones: a United States FoodNet Multicenter Retrospective Cohort Study." Antimicrobial Agents and Chemotherapy 52, no. 4 (January 22, 2008): 1278–84. http://dx.doi.org/10.1128/aac.01509-07.

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ABSTRACT Patients with typhoid fever due to Salmonella enterica serotype Typhi strains for which fluoroquinolones MICs are elevated yet that are classified as susceptible by the current interpretive criteria of the Clinical and Laboratory Standards Institute may not respond adequately to fluoroquinolone therapy. Patients from seven U.S. states with invasive Salmonella serotype Typhi infection between 1999 and 2002 were enrolled in a multicenter retrospective cohort study. Patients infected with Salmonella serotype Typhi isolates with ciprofloxacin MICs of 0.12 to 1 μg/ml (decreased ciprofloxacin susceptibility but not resistant to ciprofloxacin [DCS]) were compared with patients infected with isolates with ciprofloxacin MICs <0.12 μg/ml for fever clearance time and treatment failure. Of 71 patients, 30 (43%) were female and 24 (34%) were infected with Salmonella serotype Typhi with DCS; the median age was 14 years (range, 1 to 51 years). Twenty-one (88%) of 24 isolates with DCS were resistant to nalidixic acid. The median antimicrobial-related fever clearance times in the DCS and non-DCS groups were 92 h (range, 21 to 373 h) and 72 h (range, 19 to 264 h) (P = 0.010), respectively, and the fluoroquinolone-related fever clearance times in the DCS and non-DCS groups were 90 h (range, 9 to 373 h) and 64 h (range, 34 to 204 h) (P = 0.153), respectively. Four (17%) of 24 patients in the DCS group and 2 (4%) of 46 patients in the non-DCS group (relative risk, 2.5; 95% confidence interval, 1.2 to 5.1) experienced treatment failure. Associations persisted after adjustment for potential confounders. We demonstrate that patients infected with Salmonella serotype Typhi isolates with DCS show evidence of a longer time to fever clearance and more frequent treatment failure. Nalidixic acid screening does not detect all isolates with DCS.

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Kim, Daniel H., Judith A. Murovic, Robert Tiel, and David G. Kline. "Management and outcomes in 353 surgically treated sciatic nerve lesions." Journal of Neurosurgery 101, no. 1 (July 2004): 8–17. http://dx.doi.org/10.3171/jns.2004.101.1.0008.

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Object. This is a retrospective analysis of 353 surgically treated sciatic nerve lesions in which injury mechanisms, location, time to surgical repair, surgical techniques, and functional outcomes are reported. Results are presented to provide guidelines for management of these injuries. Methods. One hundred seventy-five patients with buttock-level and 178 with thigh-level sciatic nerve injury were surgically treated at the Louisiana State University Health Sciences Center between 1968 and 1999. Buttock-level injury mechanisms included injection in 64 patients, hip fracture/dislocation in 26, contusion in 22, compression in 19, gunshot wound (GSW) in 17, hip arthroplasty in 15, and laceration in 12; at the thigh level, GSW was the cause in 62 patients, femoral fracture in 34, laceration in 32, contusion in 28, compression in 12, and iatrogenic injury in 10. Patients with sciatic nerve divisions in which positive intraoperative nerve action potentials (NAPs) were found underwent neurolysis and attained at least Grade 3 functional outcomes in 108 (87%) of 124 and in 91 (96%) of 95 buttock- and thigh-level tibial divisions, respectively, compared with 84 (71%) of 119 and 75 (79%) of 95, respectively, in the peroneal divisions. For suture repair, recovery to at least Grade 3 occurred in eight (73%) of 11 buttock-level and in 27 (93%) of 29 thigh-level tibial division injuries, and in three (30%) of 10 buttock-level and 20 (69%) of 29 thigh-level peroneal division lesions. For graft repair, good recovery occurred in 21 (62%) of 34 and in 43 (80%) of 54 buttock- and thigh-level tibial divisions, respectively, even in proximal repairs requiring long grafts, and in only nine (24%) of 37 and 22 (45%) of 49 buttock- and thigh-level peroneal division lesions, respectively. Conclusions. Surgical exploration and neurolysis after positive NAP readings, or repair with sutures or grafts after negative NAP results are worthwhile in selected cases.

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Twist, Craig, Jamie Highton, Matthew Daniels, Nathan Mill, and Graeme Close. "Player Responses to Match and Training Demands During an Intensified Fixture Schedule in Professional Rugby League: A Case Study." International Journal of Sports Physiology and Performance 12, no. 8 (September 2017): 1093–99. http://dx.doi.org/10.1123/ijspp.2016-0390.

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Player loads and fatigue responses are reported in 15 professional rugby league players (24.3 ± 3.8 y) during a period of intensified fixtures. Repeated measures of internal and external loads, perceived well-being, and jump flight time were recorded across 22 d, comprising 9 training sessions and matches on days 5, 12, 15, and 21 (player exposure: 3.6 ± 0.6 matches). Mean training loads (session rating of perceived exertion × duration) between matches were 1177, 1083, 103, and 650 AU. Relative distance in match 1 (82 m/min) and match 4 (79 m/min) was very likely lower in match 2 (76 m/min) and likely higher in match 3 (86 m/min). High-intensity running (≥5.5 m/s) was likely to very likely lower than match 1 (5 m/min) in matches 2–4 (2, 4, and 3 m/min, respectively). Low-intensity activity was likely to very likely lower than match 1 (78 m/min) in match 2 (74 m/min) and match 4 (73 m/min) but likely higher in match 3 (81 m/min). Accumulated accelerometer loads for matches 1–4 were 384, 473, 373, and 391 AU, respectively. Perceived well-being returned to baseline values (~21 AU) before all matches but was very likely to most likely lower the day after each match (~17 AU). Prematch jump flight times were likely to most likely lower across the period, with mean values of 0.66, 0.65, 0.62, and 0.64 s before matches 1–4, respectively. Across a 22-d cycle with fixture congestion, professional rugby league players experience cumulative neuromuscular fatigue and impaired match running performance.

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Calvo Caravaca, Alfonso Luis, and María Pilar Canedo Arrillaga. "Casos escogidos de Derecho antitrust europeo." Estudios de Deusto 54, no. 1 (May 23, 2014): 285. http://dx.doi.org/10.18543/ed-54(1)-2006pp285-373.

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Caso N.º 1. Ententes: Dec.Com. 7 abril 2004, Société Air France/Alitalia Linee Aeree Italiane SpA, DO L 362 de 9 diciembre 2004 Caso N.º 2. Ententes: STJCE 29 abril 2004, C-359/01 P, British Sugar plc/Comisión Caso N.º 3. Ententes: STPI de 29 de abril de 2004, Tokai carbón Co. Ltd y otros/Comisión de las Comunidades Europeas As. T-236/01, T-239/01, T-244/01, T-245/01, T-246/01, T-251/01 y T-252/01 Caso N.º 4. Ententes: Sentencia del Tribunal de Primera Instancia 15 junio 2005, Graphites spéciaux, As. T-71/03, T-74/03, T-87/03 y T-91/03 Caso N.º 5. Ententes: STPI 8 julio 2004, Mannesmannröhren-Werke/ Comisión, T-44/00; STPI 8 julio 2004, Corus/Comisión, T-48/00; STPI 8 julio 2004, Dalmine/Comisión, T-50/00; STPI 8 julio 2004, asuntos acumulados JFE Engineering/Comisión, T-67/00, Nippon Steel/Comisión, T-68/00, JFE Steel/Comisión, T-71/00, y Sumitomo Metal Industries/ Comisión, T-78/00 Caso N.º 6. Ententes: Dec.Com. 9 diciembre 2004, Cloruro de colina, DO L 190 de 22 julio 2005. Caso N.º 7. Ententes: STJCE 28 junio 2005, Dansk Rørindustri A/S (C-189/02 P), Isoplus Fernwärmetechnik Vertriebsgesellschaft mbH y otros (C-202/02 P), KE KELIT Kunststoffwerk GmbH (C-205/02 P), LR af 1998 A/S (C-206/02 P), Brugg Rohrsysteme GmbH (C-207/02 P), LR af 1998 (Deutschland) GmbH (C-208/02 P) y ABB Asea Brown Boveri Ltd (C-213/02 P)/Comisión, Tubos de calefacción urbana (tubos preaislados), Asuntos acumulados C-189/02 P, C-202/02 P, C-205/02 P a C-208/02 P y C-213/02 P Caso N.º 8. Ententes: STPI 18 julio 2005, Scandinavian Airlines System AB/Comisión, T-241/01 Caso N.º 9. Ententes: STPI (Sala Segunda) de 27 de julio de 2005, Asuntos acumulados T-49/02 a T-51/02, Brasserie nationale SA (anteriormente Brasseries Funck-Bricher y Bofferding), Brasserie Jules Simon et Cie SCS y Brasserie Batín SNC v. Comisión de las Comunidades Europeas Caso N.º 10. Ententes: Comunicación publicada de conformidad con el artículo 27, apartado 4, del Reglamento (CE) n.º 1/2003 del Consejo, en los asuntos COMP/C2/3912-BUMA y COMP/C2/39151-SABAM (Acuerdo de Santiago-COMP/C2/38126, DO C 200 de 17 agosto 2005, pp. 11-12) Caso N.º 11. Ententes: STPI 15 septiembre 2005, DaimlerChrysler AG/ Comisión, T-325/01 Caso N.º 12. Abuso de posición dominante: Dec.Com. 24 marzo 2004, Microsoft Europe, COMP/C-3/37.792: Noción de abuso de posición dominante (la tensión entre el Derecho de la competencia y el Derecho de la propiedad intelectual) Caso N.º 13. Abuso de posición dominante: Dec. Com. 20 octubre 2004, Deutsche Post AG y RFA, COMP/38.745: Abuso de posición dominante cometido por el operador postal histórico de Alemania, por el hecho de una disposición legislativa que deberá ser modificada Caso N.º 14. Abuso de posición dominante: STPI 26 enero 2005, Piau/ Féderation Internationale de Football Association (FIFA), T-193/02, Rec., p. I-1113: Posición dominante colectiva Caso N.º 15. Abuso de posición dominante: Dec.Com. 22 junio 2005, Coca-Cola, COMP/A.39.116/B2, DO L 253 de 29 septiembre 2005: Decisión compromiso (Coca-Cola se compromete a no abusar de su posición dominante y se libra de toda sanción) Caso N.º 16. Concentraciones: Decisión de la Comisión 19 julio 2004, SONY/BMG, M. 3333 Caso N.º 17. Concentraciones: Dec.Com. 15 julio 2005, Procter & Gamble/ Gillette, M. 3732 Caso N.º 18. Concentraciones: Dec.Com. 29 julio 2005, Maersk/Ponl, M. 3829 Caso N.º 19. Concentraciones: STJCE 15 febrero 2005, Tetra Laval, C-12/03P, Rec., p. I-1113. Caso N.º 20. Concentraciones: STPI 21 septiembre 2005, EDP/Comisión, T-87/05

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Mahmoud, Reem Thaker, Aziz Ibrahim Abdulla, and Ammar S. Khazaal. "Behavior of Timber Beams Strengthened by Jute Fibers." Journal of advanced Sciences and Engineering Technologies 3, no. 1 (January 3, 2020): 1–20. http://dx.doi.org/10.32441/jaset.03.01.01.

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The study involves strengthening timber beams by known jute fibers with various forms of strengthening and comparison the bending test results with the control beams and beams strengthened by steel plates. Twenty-two timber specimens with dimensions (70×100×1000) mm are divided into eight groups and loaded under a one-point load. The work is carried out to study the flexural and shear strengthening effects on behavior of the tested beams. Four specimens wrapped in U technique in single and double layers, along the whole length of the beam in full and strips wrapping technique, seven beams bonded in full and spiral configuration, seven timber specimens wrapped in flexural strengthening technique with single and multiple layers, and two samples strengthened by steel plates. The results show that jute fibers strengthening are improved the ultimate loads of timber beams by between (30%-101%) compared with the control beams for different types of strengthening and by about (80%, 85%) using steel plates strengthening. On the other hand, the mid-span deflection are decreased by between (28%-45%) at the same load. Furthermore, it is found that the highest ultimate load deflection is when the beam wrapped in full strengthening technique. The ductility, stiffness, toughness at yield load and toughness at ultimate load are increased by between (21%-51%), (10%- 73%), (45%-373%), and (57%-401%), respectively. The jute fibers strengthening have high elasticity performance and prove that the jute fibers materials have a large potential to act as a structural strengthening material.

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Feld, J., O. Elkayam, A. Druyan, T. Reitblat, A. Balbir-Gurman, A. Hadad, T. Gazitt, et al. "POS0974 IMPROVEMENT IN THE DIAGNOSTIC DELAY OF AXIAL SPONDYLOARTHRITIS, RESULTS FROM REAL WORLD DATA." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 753.1–753. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1802.

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Background:Diagnostic delay is a major challenge in axial spondyloarthritis (axSpA) with an extended interval of 8-10 years in Europe and 14 years in the United States between symptom onset and disease diagnosis (1, 2).Objectives:To assess the delay in the diagnosis of axSpA over time in a real world axSpA cohort diagnosed in the last 3 decades and to evaluate factors associated with this delay.Methods:A cohort of axSpA patients was recruited from a national multicenter registry of inflammatory arthritis. This cohorts’ demographic, clinical and diagnostic variables were studied. The diagnostic delay was defined as the time interval between the year of first symptom and year of diagnosis. The mean and median diagnostic delay were calculated. A survival analysis was performed evaluating the association between the demographic, clinical and diagnostic variables on the diagnostic delay.Results:Of the 373 axSpA patients in the registry, 198 (47%) are men. Ankylosing spondylitis fulfilling New York criteria was diagnosed in 73% of the patients. HLA-B*27 positivity was found in 64% of patients. The majority of the patients (63%) reported symptom onset between the age of 21-45, 21% before the age of 21 and 16% after the age of 45. Nine percent were diagnosed before the age of 21, 28% between 21-30, 23% between 31-40, 21% between 41-50 and 18% after the age of 50. One hundred and ten patients were diagnosed before 2000, 133 between 2001-2009 and 130 between 2010-2020. The mean and median delay in diagnosis was 9.1, 6 (±8.4) years when diagnosed before 2000, 5, 4 (±4.1) years when diagnosed 2001-2009, and 2, 1 (±1.5) years when diagnosed 2010-2020, respectively (graph 1). The only variable which was found to be associated with a shorter delay was the interval between symptom onset and first rheumatology consult: HR of 5.86 (4.3-8, p<0.001) if the rheumatology visit was within the first year of symptoms, HR 3.5 (2.4-5, p<0.001) if assessed 2-3 years after symptom onset. Additionally, age <21 at symptom onset was associated with a shorter delay (p=0.005). Sex, type of axSpA (radiographic vs. non radiographic axSpA), level of education, and HLA-B*27 positivity were not associated with a delay in diagnosis.Conclusion:Delay in axSpA diagnosis has significantly improved in this real-world cohort during the last decade. The most significant factor associated with a faster diagnosis was the time of the first rheumatology consult relative to symptom onset. Increasing the awareness of disease manifestations and early referral to a rheumatology service can improve the diagnosis delay of axSpA.References:[1]Sorensen J, Hetland ML, all departments of rheumatology in D. Diagnostic delay in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: results from the Danish nationwide DANBIO registry. Ann Rheum Dis. 2015;74(3):e12.[2]Deodhar A, Mittal M, Reilly P, Bao Y, Manthena S, Anderson J, et al. Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay. Clin Rheumatol. 2016;35(7):1769-76.Graph 1.The improvement in the delay in diagnosis of axial spondyloarthropathy over the last 3 decadesDisclosure of Interests:None declared.

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Karalapillai, Dharshi, Laurence Weinberg, Philip J. Peyton, Louise Ellard, Raymond Hu, Brett Pearce, Chong Tan, et al. "Frequency of hyperoxaemia during and after major surgery." Anaesthesia and Intensive Care 48, no. 3 (May 2020): 213–20. http://dx.doi.org/10.1177/0310057x20905320.

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The oxygen concentration (FiO2) and arterial oxygen tension (PaO2) delivered in patients undergoing major surgery is poorly understood. We aimed to assess current practice with regard to the delivered FiO2 and the resulting PaO2 in patients undergoing major surgery. We performed a retrospective cohort study in a tertiary hospital. Data were collected prospectively as part of a larger randomised controlled trial but were analysed retrospectively. Patients were included if receiving controlled mandatory ventilation and arterial line monitoring. Anaesthetists determined the FiO2 and the oxygenation saturation (SpO2) targets. An arterial blood gas (ABG) was obtained 15–20 minutes after induction of anaesthesia, immediately before the emergence phase of anaesthesia and 15 minutes after arrival in the post-anaesthesia care unit (PACU). We defined hyperoxaemia as a PaO2 of >150 mmHg and included a further threshold of PaO2 >200 mmHg. We studied 373 patients. The median (interquartile range (IQR)) lowest intraoperative FiO2 and SpO2 values were 0.45 (IQR 0.4–0.5) and 97% (IQR 96–98%), respectively, with a median PaO2 on the first and second ABG of 237 mmHg (IQR 171–291 mmHg) and 189 mmHg (IQR 145–239 mmHg), respectively. In the PACU, the median lowest oxygen flow rate was 6 L/min (IQR 3–6 L/min), and the PaO2 was 158 mmHg (IQR 120–192 mmHg). Hyperoxaemia occurred in 82%, 73% and 54% of participants on the first and second intraoperative and postoperative ABGs respectively. A PaO2 of >200 mmHg occurred in 64%, 41% and 21% of these blood gases, respectively. In an Australian tertiary hospital, a liberal approach to FiO2 and PaO2 was most common and resulted in a high incidence of perioperative hyperoxaemia.

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Cavalieri, Sergio, Marco Spinetta, Domenico Zagaria, Marta Franchi, Giulia Lavazza, Floriana Nardelli, Alessandro Serafini, et al. "The impact of COVID-19 pandemic on radiology residents in Northern Italy." European Radiology 31, no. 9 (March 23, 2021): 7077–87. http://dx.doi.org/10.1007/s00330-021-07740-0.

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Abstract Objectives To assess changes in working patterns and education experienced by radiology residents in Northwest Italy during the COVID-19 pandemic. Methods An online questionnaire was sent to residents of 9 postgraduate schools in Lombardy and Piedmont, investigating demographics, changes in radiological workload, involvement in COVID-19-related activities, research, distance learning, COVID-19 contacts and infection, changes in training profile, and impact on psychological wellbeing. Descriptive and χ2 statistics were used. Results Among 373 residents invited, 300 (80%) participated. Between March and April 2020, 44% (133/300) of respondents dedicated their full time to radiology; 41% (124/300) engaged in COVID-19-related activities, 73% (90/124) of whom working in COVID-19 wards; 40% (121/300) dedicated > 25% of time to distance learning; and 66% (199/300) were more involved in research activities than before the pandemic. Over half of residents (57%, 171/300) had contacts with COVID-19-positive subjects, 5% (14/300) were infected, and 8% (23/300) lost a loved one due to COVID-19. Only 1% (3/300) of residents stated that, given the implications of this pandemic scenario, they would not have chosen radiology as their specialty, whereas 7% (22/300) would change their subspecialty. The most common concerns were spreading the infection to their loved ones (30%, 91/300), and becoming sick (7%, 21/300). Positive changes were also noted, such as being more willing to cooperate with other colleagues (36%, 109/300). Conclusions The COVID-19 pandemic changed radiology residents’ training programmes, with distance learning, engaging in COVID-19-related activities, and a greater involvement in research becoming part of their everyday practice. Key Points • Of 300 participants, 44% were fully dedicated to radiological activity and 41% devoted time to COVID-19-related activities, 73% of whom to COVID-19 wards. • Distance learning was substantial for 40% of residents, and 66% were involved in research activities more than before the COVID-19 pandemic. • Over half of residents were exposed to COVID-19 contacts and less than one in twenty was infected.

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Frank, Jason, Emily Sholtz, Casey Neill, and Jon De Jong. "152 Effects of dietary lactose level on nursery pig performance." Journal of Animal Science 97, Supplement_2 (July 2019): 86–87. http://dx.doi.org/10.1093/jas/skz122.157.

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Abstract Lactose is a critical nutrient in post weaning diets to help pigs transition from sows’ milk to dry feed. The objective of this study was to evaluate the effects of increasing dietary lactose level on nursery pig performance. For this trial 1,080 weaned pigs (PIC 359 x 1050; BW = 6.24 kg; 21 d) were fed 5 lactose programs using a feed budget. Program A = 24, 18, 7%; B = 20, 14, 5%; C =16, 10, 3%; D = 12, 6, 1%; and E = 8, 2, 0% lactose for Phase 1, 2, and 3; respectively. The feed budget for Phase 1 (d 0–7), 2 (d 7–14), and 3 (d 14–20) was 0.91, 3.4, and 4.5 kg/pig; respectively. A common Phase 4 (d 20–48) diet (0% lactose) was fed ad libitum. There was a quadratic response to lactose level in treatments A through E for Phase 1 ADFI (89, 71, 73, 73, 89 g/d; respectively, P = 0.034) and G:F (1.09, 1.33, 1.14, 1.15, 0.91; respectively, P = 0.042). Treatment A through E Phase 1 ADG was 100, 95, 91, 82, and 82 g/d, and Phase 2 ADG (Linear, P = 0.023) was 322, 313, 318, 304, and 295 g/d; respectively. The result was a linear trend for increased BW at the end of Phase 2 (P = 0.10) for treatments A through E (9.21, 9.10, 9.16, 9.00, 8.86 kg; respectively). Although feed cost/pig increased as lactose level increased (Linear, P = 0.041), there was no significant response in margin over feed cost/pig during the overall nursery period for treatments A through E ($15.31, $16.41, $16.22, $15.87, $16.04; respectively). In conclusion, pig performance improved during Phase 1 and 2 with increasing level of dietary lactose. These results confirm previous research showing the importance of dietary lactose in weaned pig diets.

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Kouroukis, C. Tom, Andrew Belch, Michael Crump, Elizabeth Eisenhauer, Randy D. Gascoyne, Ralph Meyer, Reinhard Lohmann, et al. "Flavopiridol in Untreated or Relapsed Mantle-Cell Lymphoma: Results of a Phase II Study of the National Cancer Institute of Canada Clinical Trials Group." Journal of Clinical Oncology 21, no. 9 (May 1, 2003): 1740–45. http://dx.doi.org/10.1200/jco.2003.09.057.

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Purpose: To determine the response rate and toxicity of flavopiridol in patients with previously untreated or relapsed mantle-cell lymphoma. Patients and Methods: Adult patients with previously untreated or in first or second relapse of previously responsive mantle-cell lymphoma were given flavopiridol 50 mg/m2/d by intravenous bolus for 3 consecutive days every 21 days with antidiarrheal prophylaxis. Flavopiridol was continued until disease progression, unacceptable toxicity, or stable disease for four cycles. Disease was reassessed every two cycles. Results: From 33 registered patients, 30 were eligible after pathology review, 30 were assessable for toxicity, and 28 were assessable for response. A median of four cycles of treatment was administered; 90% of patients received at least 90% of planned dose-intensity. No complete responses were seen; three patients had a partial response (11%), 20 patients had stable disease (71%), and five patients had progressive disease (18%). The median duration of response was 3.3 months (range, 2.8 to 13.2 months). The most common toxicities were diarrhea (97%), fatigue (73%), nausea (47%), and vomiting (27%). At least one nonhematologic grade 3 or 4 toxicity was seen in 14 patients (47%). Hematologic toxicity was modest. Conclusions: Flavopiridol given as a daily bolus for 3 consecutive days every 3 weeks has modest activity as a single agent for mantle-cell lymphoma. The number of stable and partial responses that was seen indicates that it is biologically active and may delay progression. Future studies in mantle-cell lymphoma should test this agent with other active agents and using different schedules.

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Wang, Sen-Te, Li-Sheng Chen, Long-Teng Lee, and Hsiu-Hsi Chen. "Dynamic Epidemic Model for Influenza with Clinical Complications." Infection Control & Hospital Epidemiology 32, no. 5 (May 2011): 456–64. http://dx.doi.org/10.1086/658945.

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Objective.To incorporate clinical complications in the susceptible-infectious-recovered model to estimate parameters needed in dynamic changes of infectious diseases and to further evaluate the impact of disease-controlling methods.Methods.We developed a new extended epidemic model that incorporates of disease-related complications. This model was applied to empirical data on influenza during the epidemic season of 2001–2002 in Taipei County, Taiwan, to estimate the transmission parameters that were converted to the basic reproductive rate (R0). The proposed model, in conjunction with estimated parameters, was applied in quantifying the efficacy of different preventive strategies.Results.During the study period there were 5 outbreaks of influenza. The estimated transmission probability for outbreak 1 was 0.135, with corresponding estimate of R0, 2.7; for outbreak 2, 0.165, with estimated R0, 3.3; for outbreak 3, 0.15, with R0, 4.5; for outbreak 4, 0.165, with R0, 5; and for outbreak 5, 0.165, with R0 5. The efficacy of antiviral prophylaxis to reduce the total episodes was 18% (95% CI, 15%–21%) under the coverage rate of 30%, 31% (95% CI, 26%–36%) under the coverage rate of 50%, and 73% (95% CI, 59%–90%) under the coverage rate of 80%. The corresponding figures for the efficacy of vaccination were 17% (95% CI, 15%–20%), 41% (95% CI, 35%–48%), and 76% (95% CI, 61%–95%). Combination of both methods would yield efficacy of 32% (95% CI, 28%–38%), 59% (95% CI, 49%–71%), and 88% (95% CI, 66%–118%), respectively.Conclusions.We demonstrate how to apply a novel extended model to empirical surveillance data of an influenza study for estimating parameters pertaining to dynamic changes in the infection process. These parameters were further used to evaluate the impact of antiviral prophylaxis alone, vaccination alone, or the use of both methods.

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Rand, Vikki, Helen Parker, Lisa J. Russell, Julie Irving, Lisa Jones, Dino Masic, Lynne Minto, et al. "What Is the Initiating Mechanism of iAMP21 in Childhood B Cell Precursor ALL?." Blood 114, no. 22 (November 20, 2009): 581. http://dx.doi.org/10.1182/blood.v114.22.581.581.

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Abstract Abstract 581 Patients with iAMP21 (intrachromosomal amplification of chromosome 21) represent a distinct cytogenetic subgroup of childhood B cell precursor ALL (BCP-ALL; incidence ∼2%) with a poor prognosis on standard therapy (29% EFS at 5 years). From cytogenetic studies the amplification of chromosome 21 appears to be the primary genetic change, however, whether this or associated abnormalities provide the initiating event of leukaemogenesis remains to be elucidated. Currently fluorescence in situ hybridisation (FISH) with probes directed to the RUNX1 gene provides the only reliable detection method. Knowledge of the underlying genetic mechanism will lead to improved diagnosis and determine those patients at high risk of relapse who require more intensive therapy. Our previous study using genomic arrays (1Mb aCGH, n=10; NimbleGen chromosome 21 custom oligonucleotide array, n=5) identified a common region of amplification (CRA) on 21q of 6.6 Mb and a common region of deletion (CRD) of 3.3 Mb within the telomeric region in 100% and 70% of patients, respectively. However, expression profiling (Affymetrix U133A, n=8) indicated that no important genes within the CRA or CRD were differentially expressed. We now have clinical, cytogenetic and FISH data on 94 iAMP21 patients (44 F, 50 M; median age 9.5y, range 2-30); the largest iAMP21 cohort investigated to date. Higher resolution analysis of 17/94 diagnostic samples by aCGH (Agilent 185K platform) have refined these regions to 5.1 Mb and 2.5 Mb in 100% and 88% of patients, respectively. Recent genome mapping has highlighted the presence of the microRNA miR-802 within the CRA and shown this region overlaps with the Down Syndrome Critical Region at 21q22.3 encompassing the genes DSCR1, DSCR3 and DYRK1. Detailed analysis of chromosome 21 identified recurrent breakpoints centromeric of the CRD within three genes: PDE9A (n=2), COL6A2 (n=2) and DSCAM (n=2). The role of these genes in the initiation of the chromosomal instability associated with iAMP21 is currently under investigation. Global analysis of the iAMP21 genome identified an average of 13 copy number alterations (CNA) per case with recurrent deletions of the leukaemia associated genes PAX5 (n=2), IKZF1 (n=4) and CDKN2A (n=4). To determine the incidences of PAX5, IKZF1 and CDKN2A deletions among the cohort of 94 iAMP21 patients, FISH using probes targeting these genes was carried out on availabel samples. IKZF1 (exons 3-6) was deleted at the highest incidence of 21% (13/62), while CDKN2A and PAX5 were deleted at a lower incidence of 17% (12/71) and 8% (4/48), respectively. The high incidence of IKZF1 deletions found in this patient group correlates with their association with high risk ALL. We have recently reported a deletion within the PAR1 region of the sex chromosomes, centromeric of the CRLF2 gene involving CSF2RA and IL3RA, which leads to deregulated expression of CRLF2. This deletion occurred at an incidence of 23% (17/73), as determined by FISH. Among pairs of matched diagnostic and relapse samples; one had this deletion at both diagnosis and relapse while the second had a deletion in the diagnostic sample only. Gain of an additional × chromosome was identified in 28% (18/65). Of note is that the 3 aberrations: abnormalities of chromosome 21, gain of the × chromosome and high incidence of deletions centromeric of CRLF2 in this patient group mirror the findings in Down Syndrome (DS) ALL, although we have not identified any mutations of the JAK2 kinase domain among this cohort of iAMP21 patients to date. This genome-wide study provides further support for the proposal that amplification of genes within the CRA on chromosome 21 is the primary event driving leukaemogenesis in iAMP21 patients. It has also highlighted that the 3 abnormalities in common with DS ALL and/or deletions of IKZF1, which all occur at a high incidence, contribute towards the progression of this high risk subtype of childhood BCP-ALL. Disclosures: No relevant conflicts of interest to declare.

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Lee, S., H. Ryoo, S. Bae, H. Song, M. Kim, K. Lee, W. Lee, K. Park, J. Kim, and J. Baek. "Fixed dose rate infusion of gemcitabine and UFT combination chemotherapy in patients with advanced biliary cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15581-e15581. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15581.

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e15581 Background: Biliary cancer is diagnosed at advanced stage and recurrence is common after surgical resection. Gemcitabine and UFT combination chemotherapy showed promising results in advanced pancreatic cancer(APC) and fixed dose- rate(FDR) infusion(10mg/m2/min) of gemcitabine is more effective than 30min-infusion in APC patients. We conducted a prospective multicenter phase II study to evaluate the efficacy and toxicity of FDR gemcitabine and UFT combination chemotherapy in advanced biliary cancer(ABC) patients. We evaluated the quality of life(QOL) and relationship between treatment outcome and polymorphisms of DNA repair gene such as RecQ1, RAD54L, XRCC1 and ATM. Methods: We included the chemo-naive patients with measurable metastatic or recurrent biliary adenocarcinoma except gall bladder cancer. Patients received gemcitabine infusion of rate of 10mg/m2/min on day 1, 8, and 15 plus oral UFT (400mg/m2) on day 1 to 21. We used modified PCR-RFLP method to evaluate the polymorphism of DNA repair gene. The primary endpoint was response rate. Results: From October 2006 to March 2008, 47 patients were enrolled and 33 of them were included in this analysis. Median age was 58 years(range 33–73 years) and 18 patients were male. Partial response was 24.2% and disease control rate was 51.5%. The estimated median time to progression(TTP) was 87 days(95% CI 51–123). Median overall survival was 243 days(95% CI 114–372). Grade 3/4 neutropenia was observed in 12 of 33 patients(36.4%) and 17 times of 114 cycles of chemotherapy(14.9%). No febrile neutropenia was observed. Grade 3/4 thrombocytopenia occurred in 5 patients(15.2%). Non-hematologic toxicities were mild. Polymorphism of XRCC1 was related to TTP(TTP of wild, heterozygous variant and homozygous variant type was 162, 71 and 25 days, respectively. p=0.0039). QOL as a secondary endpoint was not analyzed at this time. Conclusions: FDR infusion of gemcitabine and UFT combination chemotherapy in chemo-naïve patients with ABC is a well-tolerated and effective regimen. No significant financial relationships to disclose.

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Setogute, Yone De Camargo, Frederico Costa, Micelange Carvalho Sousa, Pablo Diego Lima, Luciana Carvalho, Elizabeth Santos, Brenda Pires Gumz, et al. "Low energy amplitude modulated radiofrequency electromagnetic fields to show antitumor effect in combination with standard treatment or as monotherapy in patients with advanced hepatocellular carcinoma." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 332. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.332.

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332 Background: Exposure to amplitude-modulated radiofrequency electromagnetic fields (EMF) in immortalized hepatocellular carcinoma (HCC) cell cultures and xenograft models demonstrated anti-tumor effect. Patients with advanced HCC exposed to systemic EMF showed objective response with potential survival benefit. Methods: An open-label, single center, prospective clinical protocol was performed in advanced HCC patients as an initial, second or third treatment modality. Systemic exposure to EMF modulated at patient-specific frequencies was applied as an add-on strategy (combination) to systemic conventional treatment or as a single therapeutic modality. A spoon-shaped antenna placed in the oral cavity delivered EMF over 90 minutes with monthly repetitions until death or consent of withdrawal. The primary objective was overall survival (OS) in comparison with historical control group of 45 advanced patients HCC from the same institution. Retrospective radiological review was conducted by two independent radiologists for objective response (OR) using RECIST1.1 criterion. Results: From March 2018 to April 2020, 55 advanced HCC patients were submitted to 373 EMF exposures. 87% were male, median age of 67, 84% were BLCL-C, 16% were Child-Pugh B, 29% had extra-hepatic metastasis, 55% had failed previous treatment and 71% had documented radiological progression. 31(56%) patients received EMF in combination with systemic therapy (25 sorafenib, 3 lenvatinib, 3 nivolumab). 24 patients received EMF as single treatment modality. The median OS for the entire patient cohort was 11.5 months. The median OS for combination treatment was 12.0 month and the median OS for single modality was 11.3 months. The median OS for the historical control was 5.3 month. The median OS from the entire cohort and the historical control were significant different (p = 0.0026) but the median OS from combination and single modality were not (p = 0.3434). Radiological images were available from 38(69%) patients. There were 6/38 (16%) documented objective responses (1 CR and 5 PR) and 30/38 (79%) patients experienced disease control. 4/21 (19%) OR were in patients using TKIs + EMF and 2/17 (12%) OR were in patients using EMF alone. Conclusions: EMF showed objective anti-tumor effect in combination with TKI or as single modality in advanced HCC patients. EMF showed improvement in overall survival in comparison with the historical control group supporting future development as a novel systemic treatment modality in advanced HCC patients. Clinical trial information: NCT 01686412.

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Greil, R., W. Pfeifer, N. Vetter, J. Eckmayr, O. Burghuber, W. Hilbe, T. Schmid, G. Gastl, and A. Mohn-Stauder. "Multicenter phase II study evaluating docetaxel (D) and cisplatin (C) as an induction regimen prior to surgery or radiochemotherapy (RCT) with D, followed by adjuvant D in chemonaive patients with NSCLC: TAX-AT1–203." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7702. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7702.

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7702 Background: This phase II study evaluated operable and unresectable patients (pts) treated with induction chemotherapy with DC to assess the response rate and conversion to resectability. Furthermore, the feasibility and efficacy of radiosensitizing with D was tested in unresectable pts undergoing RCT. The feasibility of adjuvant D was investigated in all patients. Study Design: Pts with stages II, IIIA and IIIB NSCLC were treated with 3 cycles of 3-wkly neoadjuvant D (75 mg/m2 d 1) and C (40 mg/m2 d1, 2). Within 4 wk after induction, pts were either resected or treated with RCT (2 Gy × 5d for 6 wk) and D 20 mg/m2 wkly × 6 cycles. Within 4–8 wk after definitive RCT or surgery, 3 cycles of adjuvant D 75 mg/m2 q3wk were initiated. Adjuvant RT was allowed in non-R0 resected cases. The primary endpoint was response rate to induction; secondary endpoints included resectability after induction, progression-free survival, overall survival, and safety. Results: 77 pts were included: age 60 yr [46–76 yr], males 78%, stages (II/IIIA/IIIB: 8%/39%/52%), primary resectability n=22 (29%), primary unresectability n=55 (71%). 59 patients were evaluable after induction chemotherapy, of whom 66% achieved a PR, 23% had stable disease, and 10% progressed. The PR rate was 73% in initially resectable and 63% in initially unresectable pts. 67 pts were evaluable for resectability. 28/39 (72%) of PR patients were resectable. As a result of induction therapy, 19 pts (25%) became resectable, 18 (24%) remained resectable, 27 (35%) remained unresectable, and 3 (4%) became unresectable. Treatment had to be stopped in 11 pts during induction. Three pts, primarily unresectable (4%) died of toxicity. 53% of patients had a grade 3 or 4 toxicity. In evaluable pts, the median PFS was 350 [80–1495] days vs 192 [21–989] days for resectable and unresectable pts after induction, respectively, and overall survival was 491 vs 303 days. Conclusions: DC induction chemotherapy resulted in a promising PR rate and rate of secondary resectability. The toxicity is substantial. Results of efficacy and toxicity of radiosensitizing and adjuvant D are pending. No significant financial relationships to disclose.

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Eid Alraddadi, Husain. "THEPREVALENCE OF ENERGY DRINKS AND ADVERSE EFFECT AMONG MALE STUDENTS IN TECHNICAL AND VOCATIONAL TRAINING CORPORATION (SAUDI ARABIA) IN AL-MADINAH AL-MUNAWARA REGION IN 2021." International Journal of Advanced Research 10, no. 03 (March 31, 2022): 1070–86. http://dx.doi.org/10.21474/ijar01/14492.

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Background:There are so many adverse effects of consuming energy drinks, because of high amount of caffeine like increasing heart rate and blood pressure. Energy drink sales are rarely regulated by age and no roles in selling it unlike tobacco. Also, the prevalence of energy drinks consumption progressively increases in Saudi Arabia. This study aims to estimate the Prevalence of energy drinks and adverse effect among Male students in Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara Region in 2021. The study also aims to determine the Prevalence of energy drinks and adverse effect among Male students, to assess the association of energy drinks consumption and harmful effects (headache, insomnia and palpitation) among male students, and to find out the reason of Energy Drinks consumption among male students at Taibah university in Al-Madinah Al-Munawara in 2021. Methodology: This is a cross-sectional study conducted at Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara Region in 2021 to see the prevalence and adverse effects of energy drinks among male college students between March 2021 and august 2021.Analyses were conducted using Statistics SPSS 23.0 for windows (SPSS Inc., Chicago, IL, USA). Quantitative data were presented as the mean Â± SD & (range), and qualitative data were expressed as absolute frequencies (number) & relative frequencies (percentage). Results:Out of the invited 377 students, only 373 students filled and returned the questionnaire with a response rate of 99%. Fifty-nine-point two percent (59.2%) aged between 20- 25 years old, 31.9% were less than 20 years old and 5.6% were 26- 30 years old. 36.5% were specialized in network system management. More than two -third of the studied student(71%) drink one to three energy drink packs per week, while the other one-third is distributed between other categories(11.6% drink 4- 6 packs, 6% 7- 9 packs 3.6% 10- 12 packs, 1.5% 13- 15 packs and 3% more than 15 packs per week). Favourite type of energy drink was reported as 71.9% Code red, 21.3% Red bull, 21% Bison, and 11.7% power horse. Reasons for consuming energy drinks was because of its delicious taste in 80.5%, feeling of activism in 29.9%, to reduce fatigue and compensate for lost energy in 14.7%, to drive better in 9.6%, because of effect of advertising and commercials in 2.4%, and to imitate friends in 3.9%. Conclusion:Energy drink consumption is high among male students in Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara, Saudi Arabia. The rate of consumption is significantly associated with academic year.

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Eid Alraddadi, Husain. "THEPREVALENCE OF ENERGY DRINKS AND ADVERSE EFFECT AMONG MALE STUDENTS IN TECHNICAL AND VOCATIONAL TRAINING CORPORATION (SAUDI ARABIA) IN AL-MADINAH AL-MUNAWARA REGION IN 2021." International Journal of Advanced Research 10, no. 03 (March 31, 2022): 1070–86. http://dx.doi.org/10.21474/ijar01/14492.

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Background:There are so many adverse effects of consuming energy drinks, because of high amount of caffeine like increasing heart rate and blood pressure. Energy drink sales are rarely regulated by age and no roles in selling it unlike tobacco. Also, the prevalence of energy drinks consumption progressively increases in Saudi Arabia. This study aims to estimate the Prevalence of energy drinks and adverse effect among Male students in Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara Region in 2021. The study also aims to determine the Prevalence of energy drinks and adverse effect among Male students, to assess the association of energy drinks consumption and harmful effects (headache, insomnia and palpitation) among male students, and to find out the reason of Energy Drinks consumption among male students at Taibah university in Al-Madinah Al-Munawara in 2021. Methodology: This is a cross-sectional study conducted at Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara Region in 2021 to see the prevalence and adverse effects of energy drinks among male college students between March 2021 and august 2021.Analyses were conducted using Statistics SPSS 23.0 for windows (SPSS Inc., Chicago, IL, USA). Quantitative data were presented as the mean Â± SD & (range), and qualitative data were expressed as absolute frequencies (number) & relative frequencies (percentage). Results:Out of the invited 377 students, only 373 students filled and returned the questionnaire with a response rate of 99%. Fifty-nine-point two percent (59.2%) aged between 20- 25 years old, 31.9% were less than 20 years old and 5.6% were 26- 30 years old. 36.5% were specialized in network system management. More than two -third of the studied student(71%) drink one to three energy drink packs per week, while the other one-third is distributed between other categories(11.6% drink 4- 6 packs, 6% 7- 9 packs 3.6% 10- 12 packs, 1.5% 13- 15 packs and 3% more than 15 packs per week). Favourite type of energy drink was reported as 71.9% Code red, 21.3% Red bull, 21% Bison, and 11.7% power horse. Reasons for consuming energy drinks was because of its delicious taste in 80.5%, feeling of activism in 29.9%, to reduce fatigue and compensate for lost energy in 14.7%, to drive better in 9.6%, because of effect of advertising and commercials in 2.4%, and to imitate friends in 3.9%. Conclusion:Energy drink consumption is high among male students in Technical and Vocational Training Corporation (Saudi Arabia) in Al-Madinah Al-Munawara, Saudi Arabia. The rate of consumption is significantly associated with academic year.

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Quintas-Cardama, Alfonso, Hagop Kantarjian, Guillermo Garcia-Manero, Mark Brandt, Sherry Pierce, Gautam Borthakur, and Jorge E. Cortes. "Early Clearance of Peripheral Blood Blasts but Not White Blood Cells Is a Powerful Prognostic marker for complete Response and Overall Survival in Patients with Acute Myeloid Leukemia (AML) receiving Induction Chemotherapy." Blood 118, no. 21 (November 18, 2011): 1553. http://dx.doi.org/10.1182/blood.v118.21.1553.1553.

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Abstract Abstract 1553 Background: Most pts with AML will achieve complete remission (CR) following therapy with cytarabine and an anthracycline. Early clearance of blasts in peripheral blood (PB) has been shown to be an important prognostic factor in acute lymphoblastic leukemia. We explored the dynamics of PB blasts in pts with AML undergoing induction chemotherapy with AI (ara-C 1.5g/m2x3d and idarubicin 12mg/m2x3d) at our institution and their impact in long-term outcomes. Patients & Methods: We reviewed the dynamics of PB blasts (i.e. PB blasts=0%) or WBC (i.e. WBC≤0.1×109/dL) clearance in pts with AML receiving AI (n=486). Patients with acute promyelocytic leukemia were excluded. Pt characteristics were as follows: median age 55 yrs (range, 19–73), pts <60 yrs 44 (30%), diploid cytogenetics (n=54, 36%), poor cytogenetics (n=57, 38%), median WBC 4.9 (range, 0.3–97.4), platelets 39 (range, 2–581), hemoglobin 8.4g/dL (range, 3.3–13.2), PB blasts (15% (range, 1–96), BM blasts 45% (1–96). Results: The overall response rate (ORR=CR+CRp) was 65% (58%+7%). Forty-four (30%) pts were resistant to induction therapy. To evaluate the dynamics of PB WBC and PB blast clearance, we divided all pts in 5 groups depending on the day they cleared their WBC or blasts from PB: group 1 (0–1 days), 2 (2–3 days), 3 (4–5 days), 4 (6–8 days), and 5 (beyond day 8). A total of 21, 34, 25, 4, and 3 pts were included in groups 1 through 5. No differences in CR rates were observed across all 5 groups according to the time of clearance of PB WBC (p=0.653). Likewise, similar median overall survival (OS) rates were observed in all 5 groups regardless of the timing of PB WBC clearance (0.2). However, the timing of PB blast clearance was associated with a distinct probability of achieving CR, being 73%, 74%, 65%, 24%, AND 60% for groups 1 through 5 (p=0.003). This translated into distinctly different median OS for the 5 groups (p=0.03) (Figure 1A). When groups 1, 2, and 3 were merged and compared with the merge of groups 4 and 5, the ORR for the resulting two new groups was 71% and 32% (p<0.001) and the corresponding median OS was 40 weeks and 75 weeks (p=0.038) (Figure 1B), suggesting that early PB clearance predicts long-term outcomes. Conclusion: We have shown in a large cohort of uniformly treated pts with AML that early clearance of PB blasts (but not WBC) is an important risk factor for achievement of CR and for OS. Clearance of PB blasts should be considered in prognostication schemas for pts with AML. Disclosures: No relevant conflicts of interest to declare.

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Bomben, Riccardo, Michele Dal-Bo, Dania Benedetti, Daniela Capello, Francesco Forconi, Daniela Marconi, Francesco Bertoni, et al. "Chronic Lymphocytic Leukemia Subset Expressing Mutated IGHV3-23 Has Peculiar Clinical and Biological Features." Blood 114, no. 22 (November 20, 2009): 1256. http://dx.doi.org/10.1182/blood.v114.22.1256.1256.

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Abstract Abstract 1256 Poster Board I-278 Introduction In the last years, the B cell receptor (BCR) has become a key molecule in chronic lymphocytic leukemia (CLL), given the correlation between mutational status of immunoglobulin heavy chain variable (IGHV) genes and disease prognosis. Recently, a fraction of CLL has been shown to preferentially express specific IGHV genes, often in a non-random combination with homologous heavy chain complementarity-determining region-3 (HCDR3) and peculiar light chains. Some of these stereotyped BCR mark CLL subsets with peculiar clinical behavior regardless of IGHV mutations. These data suggest a role for BCR in defining the clinical and biological features of CLL, also beyond the mutational status of IGHV genes. Patients and Methods A HCDR3-driven clustering of 1,426 IG sequences (1,398 patients) was performed using ClustalX(1.83). Time to treatment (TTT) intervals, Rai staging, IGHV mutational status, CD38, ZAP-70, and karyotype abnormalities evaluated by FISH were available for 617 patients. Gene expression profiling (GEP) and quantitative real-time PCR experiments (QRT-PCR) were performed on purified CLL cells. Results IGHV3-23 was totally absent in 71 identified stereotyped clusters despite being the second most frequently used IGHV gene, such distribution was significantly skewed (p<0.0001), compared with the distribution of IGHV genes belonging to stereotyped BCR clusters observed in our series. Although 109/134 IGHV3-23 were mutated (M), alignment of IGHV sequences revealed a high degree of conservation in the context of the 13 AA positions involved in superantigen binding by IGHV3 subgroup genes, suggesting that the majority of M IGHV3-23 cases maintained the capacity to mediate superantigen recognition and binding. Median TTT (73 months) of 43 M IGHV3-23 CLL was significantly shorter than median TTT (253 months, p=0.0153) of 333 M CLL, as well as of 326 M CLL in which 7 cases belonging to the bad prognosis IGHV3-21/IGLV3-21 cluster were excluded (253 months, p=0.0082). Multivariate Cox proportional hazard analyses selected IGHV3-23 usage (p=0.029), Rai stage (p<0.0001) and FISH group (p<0.0001) as independent markers of disease progression for 376 M CLL, and for the cohort in which 7 M CLL from the IGHV3-21/IGLV3-21 cluster were excluded. Comparing 5 M IGHV3-23 and 22 M non-IGHV3-23 CLL for their differential GEP, 212 genes were selected, 108 up-regulated and 104 down-regulated in M IGHV3-23 CLL. Using the “Gene-Ontology Tree Machine” platform, a set of growth/tumor suppressor genes (PDCD4, TIA1, RASSF5), all down-regulated in M IGHV3-23 CLL, was constantly found in several gene-ontology categories related to apoptosis. QRT-PCR confirmed a significant down-regulation of these genes in 15 M IGHV3-23 compared to 35 M non-IGHV3-23 CLL. Given the notion that PDCD4 and TIA1 are among the genes under control of miR-15a and miR-16-1 a “Gene Set Enrichment Analysis” carried out on the 212 differentially expressed genes, confirmed that M IGHV3-23 samples were significantly deprived in genes whose expression is under control of miR-15a and miR-16-1. Accordingly, QRT-PCR experiments performed on 15 M IGHV3-23 and 35 M non-IGHV3-23 CLL revealed significant higher levels of both miR-15a (p=0.0007) and miR-16-1 (p=0.0031) in M IGHV3-23 cases. No difference was found in the distribution of patients with 13q14 deletion between M IGHV3-23 CLL and M non-IGHV3-23 CLL (p=0.19). Considering the cases used for microRNA expression experiments (data available in 47/50 cases), 8/15 M IGHV3-23 CLL bore the 13q14 deletion in more than 20% of nuclei, against 19/32 cases in the group of M non-IGHV3-23 CLL (p=0.94). Conclusion Expression of IGHV3-23 marks a subset of M CLL with a worse prognosis; such a peculiar clinical behavior may be related to superantigen stimulation combined with down-regulation of specific growth/tumor suppressor genes and up-regulation of miR-15a and miR-16-1. Disclosures No relevant conflicts of interest to declare.

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Fjellstad, C. P., M. Hägg, M. Kautonen, and R. Mandla. "POS0060-PARE RHEUMATOID ARTHRITIS IN NORWAY: A SURVEY-BASED PATIENT EXPERIENCE." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 236. http://dx.doi.org/10.1136/annrheumdis-2021-eular.966.

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Background:The Norwegian Association of Rheumatologists has established a national procedure for management of rheumatoid arthritis (RA) in Norway.1 The purpose of the procedure is to support equal and evidence-based diagnosis, care and follow-up of RA patients1. It serves as guidance to all responsible of RA patient health care. The procedure includes recognized themes in rheumatic care.2,3 The impact of the procedure on RA care in Norway is, however, unknown.Objectives:To understand the patient experience through evaluating how the national procedure for RA is being followed from the patient viewpoint. To identify gaps and areas of improvement to align the national procedure and patient experience.Methods:Members of patient organization Norwegian Rheumatism Association were invited to answer a survey on demographic and disease-specific variables, perceived health and quality of care. The survey was supported by service design patient interviews (N=14). The invitations for interviews were sent through many initiatives for a representable population.Results:The observational RA cohort constituted of N=374. The patients were on average satisfied with shared decision-making, care and follow-ups: 71 % felt their illness was under control. Patients in centralized areas were more satisfied with well-being. Diagnosis times have shortened from on average 1.7 to 1.5 year in 10 years. Patients, especially those working, were dissatisfied with rehab support. 30 % of patients felt cooperation of primary and secondary care was not satisfactory and 32 % were worried for future treatment.Table 1 shows the differences in awareness of comorbidities and regular vaccination need. Where applicable, the table also shows the percentage of patients screened. The results show that patients are aware of risks, but are not being screened for the conditions. Younger patients (< 50 years) with symptoms for less than five years were generally less aware.Table 1.Awareness of comorbidity and regular vaccination needComorbiditiesRegular vaccine needHeart diseaseLung diseaseOsteoporosisAwarenessScreenedAwarenessScreenedAwarenessScreenedAwarenessOverall (# of patients)70 % (239/342)34 % (115/342)37 % (127/342)25 % (87/342)58 % (201/344)41 % (141/343)56 % (191/344)AgeUnder 50 yrs67 % (42/63)24 % (15/63)39 % (24/62)27 % (17/63)46 % (29/63)19 % (12/63)51 % (32/63)Over 50 yrs71 % (197/279)36 % (100/279)37 % (103/280)25 % (70/279)61 % (172/281)46 % (129/280)57 % (159/281)Disease onsetUnder 5 yrs56 % (27/48)19 % (9/48)29 % (14/48)20 % (10/49)51 % (25/49)21 % (10/48)59 % (29/49)Over 5 yrs72 % (212/294)36 % (106/294)38 % (113/294)26 % (77/293)59 % (176/295)44 % (131/295)55 % (162/295)The education of patients about regular vaccines (e.g. influenza and pneumonia) could be improved. Only 56 % were aware of the need for these vaccines due to RA. When asked specifically, 73 % of patients had received an influenza vaccine and 48 % pneumonia vaccine.Conclusion:This survey examines quality of care, shared decision-making, disease awareness and planning and provides a gap analysis of patient experience and national procedure. The results show that national procedure in RA is being followed from the patient viewpoint. Patients are satisfied with care, but information on preventive care (e.g. vaccination and comorbidity awareness and screenings) could be strengthened. This could improve planning of care and the outlook, particularly for young patients.References:[1]Aga AB, Haavardsholm EA. Revmatoid artritt. Nasjonal veileder i revmatologi. 2020[2]Barber CEH, Lacaille D, Hall M, Bohm V, Li LC, Barnabe C, Hazlewood GS, Marshall DA, Rankin JA, Tsui K, English K, MacMullan P, Homik J, Mosher D, Then KL. Priorities for High Quality Care in Rheumatoid Arthritis: Results of Patient, Health Professional, and Policymaker Perspectives. J Rheumatol. 2020[3]Brekke M, Hjortdahl P, Kvien TK. Involvement and satisfaction: a Norwegian study of health care among 1,024 patients with rheumatoid arthritis and 1,509 patients with chronic noninflammatory musculoskeletal pain. Arthritis Rheum. 2001 Feb;45(1):8-Disclosure of Interests:Christian Pollock Fjellstad: None declared, Milla Hägg Consultant of: Pfizer, Moona Kautonen Consultant of: Pfizer, Randeep Mandla Shareholder of: Pfizer, Consultant of: Pfizer, Employee of: Pfizer.

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Barbulescu, A., J. Askling, K. Chatzidionysiou, H. Forsblad-D’elia, A. Kastbom, U. Lindström, C. Turesson, and T. Frisell. "OP0122 COMPARATIVE EFFECTIVENESS OF JAKI VERSUS BDMARDS; A NATIONWIDE STUDY IN RA." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 68.2–68. http://dx.doi.org/10.1136/annrheumdis-2021-eular.774.

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Background:The Janus kinase inhibitors (JAKi) have been increasingly used for the treatment of rheumatoid arthritis (RA) in Sweden, with baricitinib representing ~80% of prescriptions. Evidence regarding the comparative effectiveness of JAKis versus biologics (bDMARDs), and in particular non- tumour-necrosis-factor inhibitor (TNFi) bDMARDs, in real-life is limited.Objectives:To compare RA patients treated with bDMARDs and JAKi in Sweden, in terms of: (1) patient characteristics at treatment start; (2) proportions of patients remaining on therapy, and response rates, at 12 months.Methods:RA patients starting treatment in 2017 and 2018 with either a TNFi, rituximab, abatacept, interleukin 6 inhibitors (IL6i) or a JAKi as different lines of treatment were identified in the Swedish Rheumatology Quality Register. One patient could contribute with more than one treatment episode.Treatment response at 12 months was measured as EULAR good response, HAQ improvement >0.2 units, DAS28 and CDAI remission, and as 0 tender and swollen joint counts (28JC). Patients were classified as non-responders if they stopped treatment before evaluation due to safety or inefficacy. Responses for patients who stopped treatment due to pregnancy or death and patients on treatment but with missing response were imputed using multiple imputation.Proportions of responders and differences in proportions between treatment groups, adjusted using inverse probability of treatment weighting, were estimated using linear regression with robust standard errors.Results:JAKi were often used after bDMARDs, and less frequently prescribed in combination with methotrexate. Measured comorbidities were less frequent among JAKi initiators than among non-TNFi biologic initiators, but RA activity was similar (Table).Table 1.Patient characteristics at treatment initiationCharacteristicMedian (IQR) or N (%)AbataceptIL6iRituximabTNFiJAKiTreatment Starts6945346923497905Age63 (53-71)59 (48-70)65 (54-73)59 (47-68)60 (51-70)Female543 (78)441 (83)519 (75)2739 (78)759 (84)RA duration (years)13 (5-21)10 (5-18)12 (6-22)9 (3-17)13 (7-22)Rheum. factor535 (79)385 (73)588 (87)2405 (70)686 (77)DAS284.8 (3.9-5.6)4.9 (4.0-5.7)4.7 (3.8-5.5)4.4 (3.4-5.3)4.7 (3.9-5.7)HAQ1.3 (0.8-1.6)1.3 (0.8-1.8)1.3 (0.8-1.8)1.0 (0.5-1.4)1.3 (0.8-1.8)Tender joints5 (2-9)6 (3-10)5 (2-9)4 (2-8)6 (2-10)Swollen joints4 (2-6)4 (2-7)4 (2-7)3 (1-6)4 (2-7)ts/bDMARD line3 (2-4)3 (2-4)2 (1-4)1 (1-2)4 (2-6)At least one prev. TNFi539 (78)442 (83)457 (66)1448 (41)770 (85)At least one prev. non-TNFi271 (39)220 (41)243 (35)441 (13)584 (65)Methotrexate co-treatment264 (50)172 (40)286 (53)1708 (62)296 (40)Glucocorticoids co-treatment247 (47)186 (43)275 (51)1126 (41)389 (53)Cancer*90 (2.8)64 (2.3)363 (7.7)410 (1.8)20 (2.2)Cardio-vascular dis.*245 (7.5)123 (4.4)322 (6.8)749 (3.4)41 (4.4)Chronic respiratory dis.*303 (9.3)140 (5.0)473 (10.0)721 (3.2)50 (5.4)Diabetes*324 (9.9)216 (7.7)456 (9.7)1479 (6.7)69 (7.5)* any diagnosis within 5 years before start Adjusted differences in proportion with each response outcomeIn a crude comparison, 65% (61%-68%) of JAKi, 62% (59%-66%) of abatacept, 58% (53%-62%) of IL6i, 80% (77%-83%) of rituximab and 68% (67%-70%) of TNFi initiators remained on treatment at 12 months after start. Also, JAKi showed lower overall responder proportions than TNFi, rituximab and IL6i.After adjustment for demographic and socio-economic factors, RA disease activity, previous use of ts/bDMARDs, co-medication with glucocorticoids and methotrexate and comorbidities at baseline, no significant differences in responder proportions between JAKi and bDMARDs remained (Figure). Furthermore, the adjusted proportions of patients on treatment were higher for JAKi and rituximab than for the other bDMARDs.Conclusion:This preliminary analysis of patients treated in clinical practice found no statistically significant difference in effectiveness between JAKi and bDMARDs.Disclosure of Interests:Andrei Barbulescu: None declared, Johan Askling Grant/research support from: Abbvie, Astra-Zeneca, BMS, Eli Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB. These entities have entered into agreements with Karolinska Institutet with JA as principal investigator, mainly in the context of safety monitoring of biologics via the ARTIS national safety monitoring system, Katerina Chatzidionysiou Speakers bureau: Eli Lilly, Abbvie and Pfizer, Consultant of: Eli Lilly, Abbvie and Pfizer, Helena Forsblad-d’Elia: None declared, Alf Kastbom Employee of: Sanofi, Ulf Lindström: None declared, Carl Turesson Speakers bureau: Abbvie, Bristol-Myers Squibb, Medac, Pfizer, Roche, Consultant of: Roche, Grant/research support from: Bristol-Myers Squibb, Thomas Frisell: None declared

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Varmavuo, Ville, Johanna Rimpiläinen, Anne Nihtinen, Kaija Vasala, Maija Mikkola, Päivi Lehtonen, Taru Kuittinen, et al. "Comparison of Post-Transplant Outcomes in Non-Hodgkin Lymphoma (NHL) Patients Mobilized with or without Plerixafor Added to Chemomobilization." Blood 120, no. 21 (November 16, 2012): 4520. http://dx.doi.org/10.1182/blood.v120.21.4520.4520.

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Abstract Abstract 4520 Background: Plerixafor, a CXCR4 antagonist, is used in a combination with G-CSF with or without chemotherapy to enhance mobilization of hematopoietic stem cells (CD34+) from the bone marrow to circulation. Prior studies have shown that plerixafor may mobilize more primitive stem cells and also have impact on other cell populations too. These changes may have impact in engraftment, immunological reconstitution and post-transplant outcome. However, only limited data are available in regard to effects of plerixafor in post-transplant outcomes. Patients and methods: Eighty-nine patients with non-Hodgkin lymphoma (NHL) were included in this study. The patients received disease-specific chemomobilization (most commonly cytarabine based) with G-CSF. In addition, 33 patients (37 %) received plerixafor because of insufficient mobilization, poor collection yields or late mobilization (plerixafor group). Fifty-six patients served as controls (control group). The median age was 58 years in the plerixafor group and 57 years in the control group (p=0.515). The most common histology was diffuse large B-cell lymphoma in both groups. The proportion of patients beyond CR1 or PR1 was significantly higher (55 % vs. 32%, p=0.046) in the plerixafor group. All patients were treated with a single dose (6 mg) of pegfilgrastim after stem cell infusion. Patients were followed after high-dose chemotherapy in regard to haematopoietic engraftment and outcome. Results: The median amount of collected CD34+ cells was 3.5 × 106 CD34+ cells/kg (range 1.3 – 8.9 × 106 CD34+ cells/kg) in the plerixafor group and 4.2 × 106 CD34+ cells/kg (range 1.9 – 18.6 × 106 CD34+ cells/kg) in the control group (p=0.076). The median number of aphaeresis was two (range 1–5) in both groups (p=0.17). The median neutrophil engraftment was 10 days in both groups (range 8–81 days in the plerixafor group and 8–21 days in the control group). The median time to platelet engraftment was 14 days in both groups (range 10–165 days in the plerixafor group and 10–91 days in the control group). The incidence of neutropenic fever was comparable between the groups (71% vs. 76%, p=0.906). The median follow-up time from ASCT was 373 days (range 5–929 days) in the plerixafor group and 518 days (range 81–1175 days) in the control group (p=0.052). No difference in counts of haemoglobin, leucocytes, lymphocytes or platelets were observed at +1, +3, +6, +12 months except for haemoglobin which was significantly higher in the plerixafor group at +3 months. Progression-free survival (PFS) was 72 % in the plerixafor group and 75 % in the control group (p=0.69). Overall survival (OS) was also comparable between the groups (82 % vs. 84 %, p=0.67). Conclusions: The recovery from ASCT and outcome after ASCT seems to be comparable in lymphoma patients whether plerixafor is used or not. Prospective studies including more detailed characterisation of graft cellular content in regard to CD34+ cell subtypes, T-cell repertoire and NK-cells are needed to assess the impact of mobilization method post-transplant outcome. Disclosures: Jantunen: Genzyme: Has participated in EU Leadership meeting organized by Genzyme as well as Medical Advisory Board meeting organized by Genzyme Other, Honoraria.

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Michallet, Mauricette, Quoc-Hung Lê, Jean-Paul Vernant, Franck E. Nicolini, Jean-Luc Harousseau, Philippe Colombat, Eric Deconninck, Bruno Cazin, and Didier Blaise. "Allogeneic Hematopoietic Stem Cell Transplantation Cures CLL: A Retrospective Analysis from the SFGM-TC Registry." Blood 108, no. 11 (November 16, 2006): 2991. http://dx.doi.org/10.1182/blood.v108.11.2991.2991.

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Abstract This retrospective study concerned 471 B-CLL patients registered in the SFGM-TC registry from Apr 1,984 to Feb 2,005, who underwent either autologous transplantation (n=313, 138 F and 175 M, median age = 54, 236 PBSC and 77 BM) or allogeneic transplantation (n=158, 78 F and 80 M, median age = 49, 76 PBSC, 81 BM and 1 cord blood cell transplant from 17 related and 141 unrelated donors). Among alloT patients, 50 were ABO incompatible and 70 sex-mismatched. The median interval diagnosis-transplantation was 32 months for autoT and 51 months for alloT. Just before conditioning 302 autoT and 143 alloT were evaluated for the disease status: 100 and 26 patients were in CR, 170 and 55 were in PR, 4 and 13 in stable disease (SD), 28 and 49 in progressive disease (PD) for autoT and alloT respectively. Among alloT patients, 73 received reduced intensity conditioning (RIC) and 85 standard conditioning (72 Cyt+TBI, 33 Fluda+TBI, 23 Fluda+Bu+ATG, 8 Cyt+Bu and 21 other). Before autoT the conditioning consisted of 224 Cyt+TBI, 45 BEAM and 44 other. After alloT, 71 patients developed an aGVHD ≥ grade II and 60 developed a cGVHD (25 limited and 35 extensive). The non-relapse mortality at 1 year was 29%. With a mean follow-up of 28 months for autoT and 40 months for alloT, the probabilities of 3-year, 5-year and 8-year overall survival were 80%, 66%, 45.5% after autoT and 52%, 48% and 35% after alloT respectively. An analysis aimed to determine the percentage of long-term survivors, or patients censored on the final plateau of survival curves was performed on alloT and autoT groups. A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The percentage of long-term survivors for the autoT group was 1.2%, with a mean survival length for uncured population of 160 months. Fig A shows that both curves were close and consequently shows good adequacy and the absence of a final plateau. The percentage of long-term survivors for alloT was 34.03% (figure1). Fig B shows rather good adequacy. The study of the impact of usual prognosis factors (age, time diagnosis-transplant, sex match, HLA match, CMV status, type of conditioning, BM or PBSC, ABO compatibility and disease status before transplantation) on the percentage of long-term survivors showed that only the status of disease at transplant had a significant impact: (CR vs SD or PD, HR: 0.11 [0.02–0.5] p=0.01 and PR vs SD or PD, HR: 0.30 [0.09–0.96] p=0.04). This study pointed out the possibility of curing B-CLL patients who responded to conventional chemotherapy with allogeneic transplantation rather than with autologous transplantation. Figure Figure Figure Figure

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Lui, G., E. Noss, N. Singh, J. Andrews, J. Graf, and K. Wysham. "POS0459 UNSUPERVISED CLUSTERING IDENTIFIES UNIQUE SUBSETS OF PATIENTS IN A RACIALLY AND ETHNICALLY DIVERSE RHEUMATOID ARTHRITIS COHORT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 460.2–461. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1946.

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Background:Single biomarkers have limited utility to date in guiding RA clinical care. Machine learning algorithms may better identify and stratify RA patients with differential outcomes.Objectives:To determine if unsupervised machine learning methods can be employed in a racially and ethnically diverse RA cohort to identify clusters of patients with different disease activity trajectories, as measured by DAS28ESR.Methods:Data are derived from the longitudinal, observational University of California, San Francisco RA Cohort. Along with routine labs, medications and disease activity assessments, a multiple biomarker of disease activity (MBDA) panel was obtained at each visit. The MBDA measures 12 serum biomarkers. Four patient clusters were identified by unsupervised K-prototype clustering after collapsing all observations into a cross sectional dataset. Plots were created to display longitudinal disease activity trajectories for each cluster. Lasso regression was applied to identify biomarkers associated with DAS28ESR.Results:We identified 4 distinct clusters in our cohort (Table 1) with visually different disease activity trajectories (Fig. 1). Cluster 1 (n=116) was older (63.6±9.7), had the highest proportion of Asian participants (n=73, 63%) with the most study visits and longest disease duration. Cluster 2 (n=70) had the highest mean DAS28ESR (5.5±0.7), and the highest mean dose of prednisone (8.6±4.9 mg/day). Cluster 3 had the lowest number of participants (n=14), study visits and lowest biologic use (28.6%). Cluster 4 was the largest cluster (n=173) with the shortest disease duration (4.9±3.8 years) and highest biologic use (61.3%). In the Lasso regressions, leptin was found to have significant positive associations with DAS28ESR in the whole group as well as Clusters 2 and 4. EGF had negative associations with DAS28ESR in the whole group, Cluster 1 and 4. CRP had positive associations with DAS28ESR in the whole group and Cluster 1. YKL40 and VCAM1 were found to have significant associations in Clusters 1 and 3, respectively.Conclusion:We identified 4 unique clusters of RA patients in a racially and ethnically diverse longitudinal cohort with different disease activity trajectories and biomarkers associated with disease activity. Although additional work is needed to explore longitudinal outcomes in each cluster, the application of machine learning methods may identify unique combinations of patient and disease characteristics influencing RA clinical outcomes.Table 1.Demographics and clinical characteristics of the RA cohort. Biomarkers significantly associated with DAS28ESR were determined by Lasso regression Values listed are per standard deviation of each biomarker.Overall(N=373)Cluster 1 (N=116)Cluster 2 (N=70)Cluster 3 (N=14)Cluster 4 (N=173)Demographics:Age54.8 ± 3.663.6 ± 9.750.8 ± 14.958.2 ± 15.850.3 ± 12.1Female Sex318 (85%)101 (87%)57 (81%)11 (79%)149 (86%)Race: Hispanic/Latino181 (49%)22 (19%)47 (67%)5 (36%)107 (62%) Asian123 (33%)73 (63%)8 (11%)6 (43%)36 (21%) Black35 (9%)12 (10%)8 (11%)2 (14%)13 (8%) White & Other34 (9%)9 (7%)7 (10%)1 (7%)17 (10%)Clinical Characteristics:Rheumatoid Factor315 (85%)104 (90%)56 (80%)13 (93%)142 (82%)ACPA297 (80%)98 (85%)54 (77%)12 (86%)133 (77%)Disease Duration7.8 ± 7.613.7 ± 9.75.4 ± 4.66.7 ± 5.74.9 ± 3.8csDMARD344 (92%)108 (93%)63 (90%)13 (93%)160 (93%)Biologic DMARD185 (50%)45 (39%)30 (43%)4 (29%)106 (61%)Prednisone Dose6.7 ± 3.86.0 ± 4.08.6 ± 4.95.8 ± 1.46.3 ± 2.8Body Mass Index28.2 ± 4.526.6 ± 3.828.7 ± 3.828.0 ± 6.229.1 ± 4.7DAS28ESR4.2 ± 1.14.2 ± 1.05.5 ± 0.83.9 ± 0.83.7 ± 0.9Lasso Results:EGF-0.16*-0.41***-----0.20**Leptin0.15**--0.21*--0.21**c-reactive protein0.34**0.51***------VCAM1-------0.73*--YKL40--0.26*-------EGF: epidermal growth factor; VCAM1: Vascular cell adhesion protein 1; YKL40: Chitinase-3-like protein 1.-*p<0.05, **p<0.01, ***p<0.001Figure 1.DAS28ESR trajectory plots with 95%CIs for the whole cohort and by cluster.Acknowledgements:This work was supported by the Rheumatology Research Foundation Scientist Development Award.Disclosure of Interests:None declared

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Ono, Keiko, Hideki Tsujimura, Akiyasu Satou, Xiaofei Wang, Takeaki Sugawara, Mikiko Ise, and Kyoya Kumagai. "Retrospective Study of the Optimal CHOP Dose for Elderly Patients with Diffuse Large B-Cell Lymphoma." Blood 128, no. 22 (December 2, 2016): 4211. http://dx.doi.org/10.1182/blood.v128.22.4211.4211.

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Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of malignant lymphoma, and the number of elderly patients with DLBCL is increasing. While rituximab plus CHOP (R-CHOP) therapy is considered as the standard first-line treatment for DLBCL, elderly patients are often frail and unable to tolerate the standard dose of R-CHOP. Fifteen years ago, we conducted a prospective study to investigate optimal reduced doses of CHOP therapy for patients aged 65-79 years and those older than 79 years. We concluded that 5/6 (83%) and 7/12 (58%) doses of standard CHOP are effective and tolerable for these two age groups, respectively (Mori M, et al. Leuk Lymphoma. 2001;41:359-66). Since then, we have applied this strategy with the standard dose of rituximab. To evaluate the efficacy and tolerability of reduced R-CHOP therapy for elderly patients, we performed a retrospective analysis. Methods: We reviewed medical records of patients aged 65 years or older with newly diagnosed DLBCL, who underwent R-CHOP therapy from August 2010 to December 2013. Intravascular large B-cell lymphoma and primary central nervous system lymphoma were excluded from this study because R-CHOP therapy alone is not considered as standard for these diseases. We calculated the relative dose intensity (RDI), dividing the actually used doses of cyclophosphamide and doxorubicin by the interval between each course compared with the standard doses (750 mg/m2 cyclophosphamide and 50 mg/m2 doxorubicin every 21 days). Results: During the study period, data were collected from 100 patients (56 males and 44 females) with a median age of 74 (65-86) years. Sixty patients had advanced stages, 40 patients had a score of at least one in the Charlson comorbidity index (Charlson ME, et al. J Chronic Dis. 1987;40:373-83), 18 patients had a poor performance status (Eastern Cooperative Oncology Group performance status: ≥2), and 14 patients were older than 79 years. The overall response rate was 93%, and the complete response (CR) rate was 81%. Three-year overall survival (3-yr OS) was 78%. In comparison with the international prognostic index (IPI), 3-yr OS was 100% (IPI: low, n=26), 94% (IPI: low-intermediate, n=17), 71% (IPI: high-intermediate, n=24), and 58% (IPI: high, n=33). Hematologically adverse events were generally tolerable. No patient experienced a grade 4 hemoglobin decrease, and only four patients experienced a grade 4 platelet decrease. Although 55 patients received granulocyte colony-stimulating factor, a grade 4 leukocyte decrease was common (n=38) and febrile neutropenia (FN) was often seen (n=21). Patients who experienced FN had a significantly shorter OS (p=0.04). With a median follow up of 44.4 months, 20 patients experienced disease progression and 15 patients died after progression. Five patients remained in CR but died of other types of cancer. The other seven patients died of other causes. The median RDI was 0.81 in patients aged 65-79 years and 0.58 in patients older than 79 years. These doses were very similar to the originally intended doses of 5/6 (0.83) for younger patients and 7/12 (0.58) for older patients. The older group tended to show shorter OS (3-yr OS: 64%). However, recurrence rates of the two groups were very similar. Conclusions: This study demonstrates that rituximab plus 5/6 or 7/12 doses of CHOP therapy are effective and tolerable for elderly patients aged 65-79 years and those older than 79 years, respectively. It is noteworthy that the prognosis of patients with an IPI score of ≤2 was very satisfactory. Based on these results, the dose intensity does not have to be increased for these low risk groups. It is possible that increasing the dose intensity in high risk (IPI score: ≥3) patients improves the outcome. However, high risk patients tend to have much tumor burden and a poor performance status. In this group, higher dose chemotherapy will also increase the risk of developing FN and might be associated with inferior OS. Treatment of frail elderly patients with high-risk DLBCL is extremely challenging, and we need to gain further experience. Disclosures No relevant conflicts of interest to declare.

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Khouri, Issa F., Rima M. Saliba, Celina Ledesma, Elias J. Jabbour, Francesco Turturro, Gheath Alatrash, Sairah Ahmed, et al. "Bfr (bendamustine, fludarabine, rituximab) Nonmyeloablative Allogeneic Conditioning Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)." Blood 126, no. 23 (December 3, 2015): 2011. http://dx.doi.org/10.1182/blood.v126.23.2011.2011.

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Abstract Background: Bendamustine is a novel active agent in CLL with favorable safety profile. We recently reported the preliminary results of allogeneic stem cell transplantation (alloSCT) in lymphoma/CLL patients (pts) after BFR conditioning (Khouri et al. Blood 2014; 124:2306). Herein, we report more mature outcomes in CLL pts. Results and safety were compared with a previous regimen using FCR (fludarabine, cyclophosphamide, rituximab). Patients and Methods: We studied 89 CLL pts treated on 3 trials (one includes FCR later changed to BFR) at our center. Twenty-six (29%) pts received BFR and 63 (71%) received FCR. The BFR regimen consisted of bendamustine 130 mg/m2 IV daily on days -5 to - 3 prior to transplantation, thus substituting the cyclophosphamide in the FCR regimen. The dose and schedule of fludarabine (30 mg/m2 IV daily on days -5 to -3) and rituximab (375 mg/m2 IV on day -13 and 1000 mg/m2 on days -6, +1, +8) were similar in both regimens. Tacrolimus and mini-methotrexate were used for GVHD prophylaxis. In addition, thymoglobulin 1 mg/kg IV was given on days -2, and -1 in patients receiving a matched unrelated donor (MUD) transplant. Results: Patient characteristics were similar in both groups. This included median age (58 years in both), sex distribution, and median number of prior therapies (3 in both), % pts with β2-microglobulin >3 mg/L at study entry, refractory disease (38% in BFR vs. 48% in FCR, P=0.4), presence of 17p deletion [27% in BFR vs. (8/33) 24% in FCR], unmutated status [19/21 (90%) of BFR vs 22/24 (92%) in FCR] and peripheral blood stem cell source (92% in BFR vs. 87% in FCR). Donor/recipient CMV and sex-mismatched distributions were not significantly different between the groups. However, more patients received their transplants from unrelated donors in the BFR group than the FCR group (54% vs. 32%, P=0.05). Ten (38%) BFR pts vs 2 (3%) FCR pts did not experience severe neutropenia (P <0.001) and 21 (81%) vs 39 (63%), respectively, did not require platelet transfusions (P=0.08). Median follow-up times for BFR and FCR groups were 29 (range 19-60), and 104 (range, 34-195) months. The 3-year overall survival (OS) estimates in the BFR and FCR groups were 82% vs. 51% (P=0.03) and the 3-year progression-free survival estimates were 63% vs. 27% (P=0.001). The 3-year OS improvements were seen across the prognostic factors studied for BFR and FCR respectively: MUD (93% vs 30%), presence of 17p deletion (86% vs 50%), and age >50 years (79% vs 50%), β2-microglobulin >3 mg/L (73% vs 45%), >3 prior lines of therapy (70% vs 43%) and recent years of transplant (82% vs 47%). Treatment-related mortality was 11% and 27% (P=0.05) at 2-year. The incidence of acute grade 3 GVHD was 4% and 10% in the BFR and FCR groups, respectively, despite the higher % of MUD transplants in BFR. Grade 4 acute GVHD was not observed in either group. The 3-year incidence of extensive chronic GVHD in BFR vs FCR was 45% vs 58% (P=0.01). This difference in GVHD incidence may in part be explained by a lower absolute blood level of CD8+ T cells in BFR patients compared to the FCR group at 6 months (median 343 vs 538, respectively) and 9 months (median 208 vs 406, respectively) post alloSCT. Conclusions: This is the first study to show that conditioning in alloSCT for CLL impacts outcomes with an improved survival after BFR when compared to the FCR regimen. Disclosures No relevant conflicts of interest to declare.

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Cortelazzo, Sergio, Stefano Luminari, Monica Bellei, Maurizio Martelli, Umberto Vitolo, Luigi Rigacci, Achille Ambrosetti, et al. "A Predictive Model for Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Retrospective Analysis of 1,252 Cases Performed by the Intergruppo Italiano Linfomi (IIL)." Blood 104, no. 11 (November 16, 2004): 3261. http://dx.doi.org/10.1182/blood.v104.11.3261.3261.

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Abstract Introduction: few studies have explored the usefulness of a prognostic index specifically devised for patients with localized DLBCL. The IIL has performed a retrospective analysis of a large group of patients with limited stage DLBCL and developed a new prognostic model. Results: 1,252 patients with localized (Ann Arbor stage I-II) aggressive B-cell lymphoma (IWF: G or H, WHO:DLBCL) diagnosed from 1988 to 2002 and without CNS involvement, treated by 4 cooperative groups and 2 single institutions, are the subject of this analysis. Patient’s median age was 57 years (range, 17–91) and M/F ratio was 1.26. Clinical stage was I in 239 (19%), IE in 303 (24%), II in 356 (28%) and IIE in 354 (28%) patients, respectively. Supradiaphragmatic disease was present in 56% of patients, 13% had > 3 nodal sites, 53% had extranodal involvement, and 7% had >1 extranodal site. Bulky disease (≥10 cm) was present in 26% of patients, ECOG-PS >1 in 12% and B symptoms in 14%. Abnormal biochemical data included: elevated LDH (28%), β2-microglobulin (B2M;19%) and ESR (38%) and reduced albumin (< 3.5 g/dL) in 21% of the cases. Patients were treated with anthracyclin-containing regimens ± IF-RT. After a median follow-up of 62 months for alive patients (range 1–183 months), 3 and 5-year OS rates were 73% and 71%, respectively. By univariate analysis the following 11 variables were found to be predictive of a short survival: age ≥65 yrs (P=0,0001), stage II nodal (P=0,0001), number of nodal sites (P<0.0001), poor ECOG-PS (P<0.0001), B symptoms (P=0.0009), bulky disease (P=0.0001), elevated ESR (P=0.0001), LDH (P<0.0001), Radiotherapy (P<0.001), B2M (P=0.007) and reduced serum albumin (<0.0001). By Cox multivariate analysis, age ≥65 years (p<0.001), stage II nodal (P<0.001), high LDH (P<0.001) and bulky disease (P<0.01) were indipendent risk factors (RF) for a short survival. The prognostic model was calculated with the sum of scores assigned to each variable; a score of 2 was assigned to advanced age, high LDH, and Bulky; for Stage a score of 1 was considered for stage Ie-IIe and 2 for stage II nodal. Three groups of patients with a different probability of survival (P<0.000001) were identified. Patients at low (Score 0–1; 387 pts), intermediate (Score 2–3; 484 pts) or high risk (Score 4–8; 381 pts) had a 5 years OS of 87%, 77%, 51% respectively. The predictive performance of the model was internally validated through a non parametric Bootstrap method and through residues’ analysis. Conclusions: This prognostic model, developed and validated on a very large series of patients with localized DLBCL, will allow us to select appropriate therapeutic approaches on the basis of different risk categories.

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Nadeem, Muhammad, Naomi Galili, Muhammad Mumtaz, Peter Daya, Jason Cheskis, and Azra Raza. "Survival Analysis of Myelodysplastic Syndrome (MDS) Patients with Abnormal Karyotype - A Single Group Experience." Blood 120, no. 21 (November 16, 2012): 4952. http://dx.doi.org/10.1182/blood.v120.21.4952.4952.

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Abstract Abstract 4952 Introduction: MDS are a heterogeneous group of hematologic disorders associated with clonal evolution of abnormal erythroid, myeloid and megakaryocytic lineages. Risk of transformation to acute myeloid leukemia (AML) is determined by IPSS score. Common chromosomal aberrations include abnormalities of 5, 7, 8, 20 and Y. The present survival analysis is unique in that only one team of experts was involved in diagnosis and management of these patients over more than two decades. Material and Methods: Data of patients with abnormal karyotype either at first presentation or during the course of MDS was collected retroactively. FAB, IPSS and WHO classification were used. Dates of death were retrieved from social security death index. Statistical analyses were performed by using SPSS version 18. Results: Of 709 patients with abnormal karyotypes, 292(41%) were classified as RA (or refractory cytopenias), 80 (11%) RARS, 253(36%) RAEB, 45(6%) CMMoL and 34(5%) RAEB-t and 5 (1%) were unclassified. There were 271 (37%) females and 438 (63%) males with a median age of 67 yrs and 68 yrs respectively. The most frequent abnormalities affected chromosome 5 (279 or 40%); del5q/-5 with other changes was seen in 233 (83. 5 %) and isolated del5q/-5 in 79 (28. 3%). Chromosome 7 abnormalities were found in 181 (25. 5%) patients with 38 (21%) having isolated del7q/-7. Chromosomal 8 abnormality was seen in 174 (24. 5%) patients and 71 (41%) had isolated trisomy 8. Other frequently involved chromosomes were 20 and Y affecting 158 (22. 3%) and 55 (7. 8%) patients respectively. Complex karyotype with 3 or more chromosomal aberrations was seen in 201 (28. 3%) patients. Data on 700 patients was available for analysis when all chromosomal aberrations were considered according to various IPSS risk categories. The median survival was 73 months for low risk (74 patients), 33. 7 months for int-1 (303 patients), 13 months for int-2 (227 patients) and 11. 5 months for high risk (96 patients) (p=0. 000) groups. By cytogenetic abnormalities, the best median survival of 82 months (39/229) was seen in patients with del5q/-5 and low risk disease. Other risk groups with de5q/-5 showed 32, 11 and 9 months in int-1, int-2 and high risk disease respectively (p=<0. 05). The worst median survival was in patients with high risk disease and del7q/-7 (7. 4 months, 33/127) and in patients with complex karyotype (8 months, 55/197). Conclusion: Deletion 5q patients show the best median survival among low and int-1 risk groups. Our data show considerable improvement in median survival of high risk patients compared to the earlier reported survival (11. 5 versus 4 months) which probably reflects improvement due to the use of hypomethylating agents. This improvement in survival gains more significance when considering the fact that we have used the data of only those patients with chromosomal aberrations. Disclosures: No relevant conflicts of interest to declare.

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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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Bazarbachi, Ali, Myriam Labopin, Mohamed A. Kharfan-Dabaja, Rainer Schwerdtfeger, Liisa Volin, Jean-Henri Bourhis, Gerard Socie, et al. "Allogeneic Hematopoietic Cell Transplantation in AML with Normal Karyotype and NPM1 Mutated FLT3-ITD Negative: A Retrospective Analysis from the Acute Leukemia Working Party of EBMT." Blood 124, no. 21 (December 6, 2014): 1230. http://dx.doi.org/10.1182/blood.v124.21.1230.1230.

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Abstract Background: NPM1 mutation, in the absence of FLT3 internal tandem duplication (FLT3-ITD), confers a survival advantage and lower risk of disease relapse in AML with normal diploid karyotype. The prognostic significance of mutated NPM1 in the setting of allogeneic hematopoietic cell transplantation (HCT) for AML has not been described. Patients and methods: we evaluated the post-transplant outcomes of 156 patients (females=83, 53.2%), median age of 54 (19.5-71) years, with normal diploid karyotype and NPM1 Mutated FLT3-ITD Negative, who underwent an allogeneic HCT between 2006 and 2012. Donor source was limited to matched-related (MRD) or matched-unrelated (MUD) donors, and cell source consisted of bone marrow (BM) or G–CSF mobilized peripheral blood stem cells (PBSC). Patient-, donor-, and disease-characteristics are summarized in Table 1. Results: the median time from diagnosis to allogeneic HCT was 310 (89-3713) days and the median follow-up from time of allografting was 32 (2-86) months. Overall, the 2-year cumulative incidence of relapse (CIR)and non-relapse mortality (NRM) were 27% (20-35) and 13% (8-19) respectively, and the 2-year cumulative incidence of chronic GVHD was 37% (29-46). Finally, the 2-year leukemia-free survival (LFS) and the 2-year overall survival (OS) were 60% (51-68) and 70% (62-77), respectively. In univariate analysis, transplantation in CR1 was associated with lower2-year CIR [CR1=14% (7-23), CR2=37% (23-51), advanced/active=48%(26-67), p=0.0009], superior2-year LFS [CR1=75%(64-86), CR2=51% (36-65),advanced/active=30%(11-49), p<0.0001] and superior2-year OS [CR1=81%(72-91), CR2=67% (54-80), advanced/active=39% (19-59), p<0.0001]. Patients allografted from unrelated donors have higher 100-day cumulative incidence of > grade 2 acute GVHD [MUD=28% (19-39)vs. MRD=12%(5-22), p=0.02]. Patients older than 54.3 years had higher 2-year cumulative incidence of NRM [20% (11-31)vs. 7%[2-14], p=0.03] and inferior 2-year OS [61%(49-72) vs. 78% (68-88), p=0.02]. In multivariable analysis using a Cox proportional-hazard model, transplantation in CR1 resulted in lower2-year CIR and superior2-year LFS and OS. Conclusions: AML disease status at allografting remains the most important predictor of post-allogeneic HCT outcomes despite expression of mutated NPM1. Survival outcomes are better when patients are transplanted in CR1>CR2>advanced/active. The impact of other molecular abnormalities in conjunction with NPM1 is yet to be established. Also, a future matched-controlled analysis comparing AML patients with mutated vs. wild-type NPM1 expression in the setting of allogeneic HCT is warranted. Table 1 variables Results N, (%) Recipient gender F=83 (53%) M=73 (47%) Donor gender F=57 (37%) M=97 (63%) [missing=2] Female donor à male recipient Yes=21 (14%) No=133 (86%) [missing=2] Donor source MRD=66 (42%) MUD=90 (58%) Cell source BM=30 (19%) PBSC=125 (80%) BM+PBSC=1 (1%) Disease status at allogeneic HCT CR1=69 (44%) CR2=64 (41%) Advanced/active=23 (15%) Preparative regimen intensity RIC=85 (54%) MAC=71 (46%) ATG use Yes=84 (54%) No=72 (46%) GVHD prophylaxis CSA+MTX=77 (49%) CSA+MMF=41 (27%) CSA alone=28 (18%) Others=8 (5%) [missing=2] Recipient CMV serology Seropositive =101 (65%) Seronegative =54 (35%) [Unknown/missing=1] Donor CMV serology Seropositive =62 (40%) Seronegative =92 (60%) [Unknown/missing=2] Donor/recipient CMV serology D+/R+=48 (31%) D+/R-=14 (9%) D-/R+=52 (34%) D-/R-=39 (26%) [Unknown/missing=3] Abbreviations : F: female, M: male, MRD: matched-related donor, MUD: matched-unrelated donor, RIC: reduced-intensity conditioning, MAC: myeloablative conditioning, CSA: cyclosporine A, MTX: methotrexate, MMF: mycophenolatemofetil, D: allograft donor, R: allograft recipient Disclosures No relevant conflicts of interest to declare.

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Soverini, Simona, Luana Bavaro, Margherita Martelli, Caterina De Benedittis, Alessandra Iurlo, Nicola Orofino, Livio Pagano, et al. "Compound BCR-ABL1 Kinase Domain Mutants: Prevalence, Spectrum and Correlation with Tyrosine Kinase Inhibitor Resistance in a Prospective Series of Philadelphia Chromosome-Positive Leukemia Patients Analyzed By Next Generation Sequencing." Blood 132, Supplement 1 (November 29, 2018): 789. http://dx.doi.org/10.1182/blood-2018-99-117166.

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Abstract Next-Generation Sequencing (NGS)-based BCR-ABL1 kinase domain (KD) mutation screening has been shown to enable greater accuracy and sensitivity and straightforward identification of compound mutants (CM) as compared to Sanger sequencing (seq). However, the prevalence of CMs has never been assessed in prospective studies, and although in vitro data suggest that many of them may be challenging for all tyrosine kinase inhibitors (TKIs) including ponatinib, attempts to correlate such data with in vivo responses have never been made. To address these issues, we have reviewed the results of routine NGS-based BCR-ABL1 KD mutation screening performed over the past 3 years. Between 2015 and 2018, we have prospectively used NGS to analyze a consecutive series of 751 Ph+ leukemia patients (pts) on TKI therapy who were eligible for BCR-ABL1 KD mutation screening according to ELN/NCCN/ESMO recommendations. The study population included 664 chronic myeloid leukemia (CML) pts with failure or warning response (chronic phase [CP], n=593; accelerated or blastic phase [AP/BP], n=71) and 87 Ph+ acute lymphoblastic leukemia (ALL) pts with relapsed/refractory disease. NGS of ≈400bp amplicons generated by nested RT-PCR was performed on a Roche GS Junior (until April 2017) or on an Illumina MiSeq (from May 2017 on) using custom protocols whose accuracy, sensitivity and reproducibility was checked by national and international (EUTOS) control rounds. Read alignment and variant calling was done using the AmpSuite software (SmartSeq srl), with a lower detection limit set to 3%. Cis or trans configuration of mutation pairs, indicating CMs or polyclonality, respectively, was determined correcting for the likelihood of PCR recombination. The 35INS insertion/truncation mutant was excluded from the analysis. NGS identified mutations in the BCR-ABL1 KD in a total of 313/664 (47%) CML pts (255/593 [43%] CP-CML and 58/71 [82%] AP/BP-CML) and 69/87 (79%) Ph+ ALL pts. Ninety-one percent of the mutations could be recognized as conferring resistance to at least one TKI on the basis of publicly available IC50 data or published reports. In 42/593 (7%) CP-CML, 6/71 (8.5%) AP/BP-CML and 12/87 (14%) Ph+ ALL pts, low burden mutations (i.e., mutations carried by a proportion of transcripts <15% - hence invisible to Sanger seq) were the only detectable mutation(s). In 21/593 (3.5%) CP-CML, 26/71 (37%) AP/BP-CML and 40/87 (46%) Ph+ ALL pts low burden mutations co-existed together with at least one dominant mutation (i.e. a mutation carried by a proportion of transcripts >15% - hence detectable by Sanger seq). Fifty-five (9.2%) CP-CML, 51 (72%) AP/BP-CML and 56 (49%) Ph+ ALL pts had ≥2 mutations (CP-CML: 1-5 mutations; AP/BP-CML: 1-6 mutations; Ph+ ALL: 1-13 mutations). Identification of CMs in pts with ≥2 mutations was fully possible (i.e., all the candidate pairs mapped within a distance of 400bp) in 71% of cases and partially possible (i.e., some, but not all the candidate pairs mapped within a distance of 400bp) in another 12% of cases. A total of 86 CMs (85 double and 1 triple) in 73 pts (21 [3.5%] CP-CML, 23 [32%] AP/BP-CML and 29 [37%] Ph+ ALL pts) could be catalogued (Figure 1A). All but two (T315I+D276G, M244V+E255K) were detected in pts who had received ≥2 TKIs and all included at least a 2nd-generation TKI-resistant mutation. The most frequent CMs were T315I+E255K, T315I+E255V, T315I+F359V, F317L+Y253H (Figure 1A). The triple CM, detected in a ponatinib-resistant pt, was F317I+Y253F+Q252H. Correlation of IC50 data with in vivo responses (the TKIs pts were clinically resistant to) confirmed only partially in vitro predictions (Figure 1B). In particular, although ponatinib was shown in vitro to be poorly effective against several CMs, only the T315I+E255V was consistently found to be associated with ponatinib failure. In conclusion, our results in a large unselected series of TKI-resistant pts analyzed by NGS show that:CMs are relatively infrequent in CP-CML, but may be a relevant issue in AP/BP-CML and Ph+ ALL;among pts with multiple mutations, those who have failed 1 line of therapy have most often polyclonality, whereas those who have failed ≥2 lines of therapy may have CMs or polyclonality;in vitro predictions of sensitivity and insensitivity based on IC50 data should be regarded with caution. In particular, the only compound mutant that we consistently found to be associated with ponatinib failure was the T315I+E255V. Supported by EUTOS 2016. Disclosures Soverini: Novartis: Consultancy; Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy. Pagano:Pfizer: Speakers Bureau; Gilead: Speakers Bureau; Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau. Gugliotta:Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Angelucci:Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC. Martinelli:Abbvie: Consultancy; Ariad/Incyte: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Calizaya, José Manuel, Gloria Isabel Monzón Alvarez, Ana Rosario Miaury Vilca, Hilda Lizbeth Pinto Pomareda, and Jose Luis Evangelista Aliaga. "SATISFACCIÓN CON LA VIDA EN GRUPOS ETARIOS DE LA CIUDAD DE AREQUIPA, PERÚ." Universidad Ciencia y Tecnología 24, no. 107 (December 24, 2020): 56–62. http://dx.doi.org/10.47460/uct.v24i107.414.

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El objetivo del estudio fue analizar el nivel de satisfacción con la vida en grupos etarios según variables sociodemográficas, se realizó en 1661 sujetos (adolescentes, jóvenes, adultos y adultos mayores) de 3 distritos de la ciudad de Arequipa, a quienes se les aplicó el cuestionario de satisfacción con la vida. Se encontró que el nivel de satisfacción de los participantes es moderado con tendencia a ser alta. Según grupo etario, los adultos mayores presentan niveles altos de satisfacción con la vida en comparación a los otros grupos y las personas que presentan mayor nivel educativo se encuentran más satisfechos con la vida. Se concluye que, los resultados guardan relación con el nivel de bienestar y calidad de vida que experimentan las personas haciendo una evaluación global positiva de su experiencia en la vida. Palabras Clave: satisfacción con la vida, grupos etarios, variables sociodemográficas. Referencias [1]J. Zanabria, «Crecimiento económico permitió disminuir la pobreza monetaria,» El Peruano, p. 3, 4 11 2019. [2]C. Cómez, G. J. Suárez, J. E. Garzón y J. A. Gómez, «El ser y el tener de los habitantes de la ciudad de Medellín como determinantes de la satisfacción con lavida.,» Revista Latinoamericana de Desarrollo Económico, vol. 1, nº 26, pp. 69-98, 2016. [3]M. Rojas, «Economía de la felicidad. Hallazgos relevantes respecto al ingreso y el bienestar,» El Trimestre Económico, vol. 76, nº 303, pp. 537-573, 2009. [4]M. Seligman y M. Csikszentmuhalyi, «Positive Psychology: An introduction,» American Psychologist, nº55, pp. 5-14, 2000. [5]M. F. Rabito y J. M. Rodríguez, «Satisfacción con la vida y bienestar psicológico en personas con Disforia de Género,» Actas Especiales Psiquiatría, vol. 44, nº 2, pp. 47-54, 2016. [6]J. Alfaro, J. Guzmán, F. Reyes, C. García, J. Varela y D. Sirlopú, «Satisfacción global con la vida y satisfacción escolar en estudiantes Chilenos,» Psykhe (Santiago), vol. 25, nº 2, pp. 1-14, 2016. [7]W. L. Arias, J. C. Huamani y T. Caycho, «Satisfacción con la vida en escolares de la ciudad de Arequipa,» Propósitos y Representaciones, vol. 6, nº 1, pp. 351-407, 2018. [8]R. Moreta, C. López, P. Gordón, W. Ortíz y I. Gaibor, «Satisfacción con la vida, bienestar psicológico y social como predictores de la salud mental en ecuatorianos,» Actualidades en Psicología, vol. 32, nº 124, pp. 112-126, 2018. [9]J. A. Fernández, M. Fernández y A. Cieza, «Los conceptos de calidad de vida, salud y bienestar analizados desde la perspectiva de la Clasificación Internacional del Funcionamiento (CIF),» Revista Española de Salud Pública, vol. 84, nº 2, pp. 169-184, 2010. [10]J. García, «Psicología positiva, bienestar y calidad de vida,» En-claves del pensamiento, vol. 8, nº 16, pp. 13-29, 2014. [11]T. Mayodormo, A. Sales, E. Satorres y J. Meléndez, «Bienestar psicológico en función de la etapa de vida, el sexo y su interacción,» Pensamiento Psicológico, vol.14, nº 2, pp. 101-112, 2016. [12]J. Murillo y F. Molero, «La Satisfacción Vital: Su relación con el prejuicio, la identidad nacional, la autoestima y el bienestar material, en inmigrantes,» ActaColombiana de Psicología, vol. 15, nº 2, pp. 99-108, 2012. [13]J. Martell, C. H. García, L. Daniel, P. Sánchez y A. Mendoza, «Estructura factorial de la escala de satisfacción con la vida y validez convergente con la escala de calidad de vida en preparatorianos mexicanos,» Revista de psicología y ciencias del comportamiento de la Unidad Académica de Ciencias Jurídicas y Sociales, vol. 9, nº 2, pp. 30-45, 2018. [14]E. Calvo y P. Beytía, «¿Cómo medir la felicidad?,» Claves de Políticas Públicas, vol. 1, nº 4, pp. 1-11, 2011. [15]M. Vallejo y M. d. P. Moreno, «Satisfacción vital y su relación con otras variables psicosociales en población española residente en Alemania,» Escritos de Psicología, vol. 9, nº 2, pp. 12-21, 2016. [16]N. Pérez y A. Alegre, «Satisfacción con la vida: predictores y moderadores.,» Psicologia positiva i benestar , vol. 1, nº 1, pp. 447-457, 2014. [17]C. A. Alvarez, A. M. Briceño, K. Álvarez, M. Abufhele y I. Delgado, «Estudio de adaptación y validación transcultural de una escala de satisfacción con la vida para adolescentes,» Revista Chilena de Pediatría, vol. 89, nº 1, pp. 51-58, 2018. [18]E. López, N. Pérez y A. Alegre, «Competencia emocional, satisfacción en contextos específicos y satisfacción con la vida en la adolescencia,» Revista de Investigación Educativa, vol. 36, nº 1, pp. 57-73, 2018. [19]M. Ramírez y S.-L. Lee, «Factores asociados a la satisfacción vital en adultos mayores de 60 años,» Polis (Santiago), vol. 11, nº 33, pp. 407-428, 2012. [20]J. Inga y A. Vara, «Factores asociados a la satisfacción de vida de adultos mayores de 60 años en Lima-Perú,» Universidad Psychology Bogotá (Colombia), vol. 5, nº 3, pp. 475-485, 2006. [21]P. Ruiz, Y. Medina, A. Zayas y R. Gómez, «Relación entre la autoestima y la satisfacción con la vida en una muestra de estudiantes universitarios,» Revista INFAD de Psicología, vol. 2, nº 1, pp. 67-76, 2018. [22]C. Merino, S. Domínguez y M. Fernández, «Validación inicial de una Escala Breve de Satisfacción con los Estudios en estudiantes universitarios de Lima,» Educación Médica, vol. 18, nº 1, pp. 74-77, 2017. [23]J. D. Polo, M. Fernández y R. G. Ramírez, «Diseño del trabajo y satisfacción con la vida,» Revista Venezolana de Gerencia, vol. 17, nº 59, pp. 466-481, 2012. [24]S. Carrasco, Metodología de la Investigación Científica. Pautas metodológicas para diseñar y elaborar el proyecto de investigación, Lima: Editorial San Marcos, 2019. [25]E. Diener, R. A. Emmons, R. J. Larsen y S. Griffin, «The Satisfaction with Life Scale.,» Journal of Personality Assessment, vol. 49, nº 1, pp. 71-75, 1985. [26]F. L. Atienza, D. Pons, I. Balaguer y M. García, «Propiedades psicométricas de la Escala de Satisfacción con la Vida en adolescentes,» Psicothema, vol. 12, nº 2, pp. 314-319, 2000. [27]D. Frias, Análisis de la consistencia interna de las puntuaciones de un instrumento de medida, Valencia: Universidad de Valencia, 2020. [28]J. L. Ventura, «Tamaño del efecto para la U de Mann-Whitney: aportes al artículo de Valdivia-Peralta et al.,» Revista chilena de neuro-psiquiatría, vol. 54, nº 4, pp. 353-354, 2016. [29]M. Tomczak y E. Tomczak, «Se revisó la necesidad de informar las estimaciones del tamaño del efecto. Una descripción general de algunas medidas recomendadas del tamaño del efecto,» Trends Sport Sciences, vol. 1, nº 21, pp. 19-25, 2014. [30]S. Domínguez, «Magnitud del efecto, una guía rápida,» Educación Médica, vol. 19, nº 4, pp. 251-254, 2018.

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Minetto, Paola, Fabio Guolo, Malgorzata Mikulska, Giordana Pastori, Livia Giannoni, Elisa Furfaro, Franca Miletich, et al. "Posaconazole for Primary Antifungal Prophylaxis in AML Patients: A Real Life Single Center Experience and a Comparison with the Historical Cohort." Blood 124, no. 21 (December 6, 2014): 5255. http://dx.doi.org/10.1182/blood.v124.21.5255.5255.

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Abstract Backgrounds and aims Prevention and prompt treatment of invasive fungal infections (IFI) in acute myeloid leukemia (AML) patients can improve overall survival not only by reducing infection-related mortality but also allowing to comply induction regimens on time. The aim of the study was to estimate efficacy and feasibility of primary antifungal prophylaxis with posaconazole (PSZ) in patients affected by acute myeloid leukemia receiving front-line chemotherapy and to optimize our clinical practice. Materials and methods From January 2013 to May 2014, 28 AML patients undergoing intensive chemotherapy and potentially eligible for bone marrow transplantation in our institute received PSZ prophylaxis for IFI. All patients received a fludarabine, cytarabine and idarubicin containing regimen as first line treatment. We performed a retrospective analysis to evaluate the efficacy and feasibility of PSZ prophylaxis; to detect factors affecting drug exposure we analyzed each period of hospitalization as a single independent event. PSZ was given at the standard dose of 200 mg for 3 times/day, concurrently with a fat snack or with at least 100 ml of an acidic drink. Because of unpredictable absorption rates PSZ serum levels (TDM) were assessed routinely according to a validated high-performance liquid chromato-graphic (HPLC) method as described. A comparison with an historical cohort with similar features who had received fluconazole (FLC) prophylaxis was made. The use of empirical or targeted antifungal therapies and the incidence of IFI were compared. Results and discussion PSZ showed a good tolerability profile with no serious adverse events clearly related to prophylaxis occurring. A median number of 2 TDM for each period of hospitalization was performed (range 2-5). The achievement of a plasmatic PSZ concentration > 0,7 mcg/mL is considered optimal for prophylaxis efficacy; in 30/47 (64%) episodes of hospitalization and treatment, with at least two TDM, the threshold PSZ serum concentration was reached, with stable plasmatic levels. Median PSZ plasmatic value at first assessment was 0.89 mcg/mL (range 0.1-3.3). Table 1 summarizes patients features and factors that might affect PSZ plasma concentrations. The strongest negative factors affecting PSZ absorption are the discontinuation of prophylaxis and the concomitant assumption of proton pump inhibitors since their negative impact is shown both in univariate and multivariate analysis. No proven IFI were observed in our cohort with only one probable IFI occurring in a patient with refractory disease who did not reach adequate serum PSZ concentration. Table 2 summarizes the comparison with our historical cohort. The risk of experiencing IFI (proven or probable) during AML treatment is significantly higher in the FLC cohort (HR: 9.488, CI: 1,404 - 64,122). Moreover, the use of targeted or empirical antifungal therapies had been significantly higher in FLC cohort (HR: 2.7, CI: 1,212 - 6,050). Our clinical experience confirms the utility and cost-effectiveness of primary prophylaxis with PSZ in AML patients receiving intensive treatment. Table 1: Factors affecting PSZ serum concentration Reached plasmatic concentration threshold (%) p(univariate) p(multivariate) All Hospitalizations 30/47 (64) - - Sex Male 17/23 (74) 0.227 - Female 13/24 (54) Disease Status Active Disease 13/27 (57) 0.014 0.156 Complete Response 17/20 (85) Mucositis None or Grade 1 25/32 (78) 0.008 0.228 Grade >=2 5/15 (33) Age <=45 years 12/21 (57) 0.543 - >45 years 18/26 (69) Concomitant PPI No 28/36 (78) 0.001 0.000 Yes 2/11 (18) Concomitant Ranitidine No 26/42 (62) 0.640 - No 4/5 (80) Concomitant Levofloxacine prophylaxis Yes 27/39 (69) 0.118 0.042 No 3/8 (38) Prophylaxis Discontinuation Never 27/36 (75) 0.009 0.003 At least for 2 dd 3/11 (27) Infectious Complications None 8/11 (73) 0.722 - At least one episode 22/36 (61) PSZ Assumption with Fat snack 5/11 (46) 0.153 0.150 Acidic drink 25/35 (71) Table 2: Historical comparison FCZ PSZ p All hospitalizations 54 47 - Median age (range) 47 (17-72) 47 (19-68) 0.560 Median ANC <500 days (range) 18 (12-35) 21 (7-30) 0.182 Infectious complications (%) 43/54 (80%) 36/47 (77%) 0.643 Proven or probable IFI (%) 16/54 (30%) 1/47 (2%) 0.000 Empirical or targeted antifungal therapy (%) 19/54 (36%) 5/47 (11%) 0.002 Disclosures No relevant conflicts of interest to declare.

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Kaur, Kiranveer, Ying Huang, Subha Raman, Eric H. Kraut, and Payal Desai. "Cardiac Injury and Microvascular Ischemia in Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 2286. http://dx.doi.org/10.1182/blood-2019-125445.

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Introduction: Myocardial ischemic injury remains an under recognized problem in patients with sickle cell disease (SCD), for which the exact prevalence remains undefined. SCD patients are known to have microvascular disease, impaired myocardial perfusion reserve and lack of typical epicardial vessel involvement based on prior data. Previous study at our institution has demonstrated that 3/22(13%) patients with clinically stable sickle cell disease had impaired myocardial perfusion reserve but no epicardial coronary artery disease. In this study, we will aim to learn prevalence of cardiac injury and microvascular ischemic disease. We will also evaluate for impact of these findings on overall survival (OS) of SCD patients. Methods: We conducted a retrospective chart review of patients with SCD seen at OSU Wexner Medical Center from July 2005 to July 2015 to identify patients who had elevated troponin-I level or cardiac MRI performed for chest pain. Clinical and laboratory data around the time of cardiac MRI and troponin elevation was collected. Abnormal MRI was defined in three ways: 1) Microvascular disease was defined by presence of subendocardial or myocardial perfusion defects and myocardial scarring. 2) Myocardial disease otherwise includes other findings suggestive but not specific for myocardial ischemia including left ventricular dysfunction, midmyocardial fibrosis, inflammation and regional wall motion abnormalities. 3) Abnormal MRI includes patients described in either 1) or 2). Kaplan-Meier (KM) method was used to evaluate the impact of microvascular disease defined in all 3 ways on OS. Proportional hazards model was fit to estimate the association between troponin elevation and OS, where troponin elevation was treated as a time-dependent variable and OS was measured from time of birth. Results: Sixty-nine (51% male; genotype Hb SS 75%, SC 16%, and Sβ-thal 9%) of 373 SCD patients had either abnormal troponin and/or had cardiac MRI done. Median age was 34 years (range 19-67 years). Of 238 patients who had troponin-I measured over this period, 18 % (n=42) had elevated troponin. 24 of 47 patients with cardiac MRI showed abnormalities described above specific for microvascular disease (n=14, 30%) and myocardial disease otherwise (n=10, 21%). We identified 22 patients with troponin measurement within 30 days before cardiac MRI. Elevated troponin levels predicted MRI abnormalities with sensitivity of 71% (95% confidence interval (CI) 42-92%) and specificity of 63% (95% CI 24-91%). The degree of troponin elevation did not correlate with the MRI abnormality. Hazard ratio of death in patients with elevated troponin was 5.1 (95% CI 2.7-9.6; p<0.0001). While the KM survival curves show lower OS in patients in abnormal MRI (p=0.74) and microvascular disease (p=0.42; Figure 1) group compared with normal MRI, the comparisons were not statistically significant. There was no difference in OS for patients with nonspecific myocardial disease findings (p=0.59). Conclusion: Over a 10-year period, the prevalence of cardiac injury as measured by elevated troponin was 18% (42/238) in patients with atypical chest pain. Among 47 patients who had cardiac MRI performed, 51% were abnormal with 30% having findings specific for microvascular cardiac disease. Troponin elevation appears to significantly increase the risk of all-cause mortality. Patient with microvascular and myocardial ischemic disease tend to have lower OS, but it did not reach statistical significance. This could be one of the potential contributing factors to high early mortality and sudden deaths in SCD patients. Further studies will be needed to elaborate on disease modifying interventions that impact survival in these patients. Disclosures Desai: Novartis: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Potomac: Speakers Bureau; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; University of Pittsburgh: Research Funding; Ironwood: Other: Adjudication Board.

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Franceschetti, Silvia, Annarita Conconi, Kathrin Aprile Von Hohenstaufen, Gloria Margiotta Casaluci, Anastasios Stathis, Alden Moccia, Michele Ghielmini, et al. "Histologic Transformation in Marginal Zone Lymphomas." Blood 120, no. 21 (November 16, 2012): 1571. http://dx.doi.org/10.1182/blood.v120.21.1571.1571.

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Abstract Abstract 1571 Background. Information concerning histologic transformation (HT) of marginal zone lymphomas (MZL) into aggressive entities is scant. We retrospectively analyzed the clinical variables at diagnosis and outcome, with special reference to HT, in a population of consecutive patients (pts) with confirmed diagnosis of MZL, including extranodal MZL (MALT lymphoma), splenic MZL (SMZL) and nodal MZL (NMZL). Patients and methods. The database of the Oncology Institute of Southern Switzerland (IOSI, Bellinzona) and of the Hematology Division of the Amedeo Avogadro University of Eastern Piedmont (Novara) includes 373 cases of MZL diagnosed and treated since 1979 to 2012: 186 MALT lymphomas (50%), 88 SMZL (23%), 36 NMZL (10%). Sixty-three patients (17%) could not be properly classified (uMZL): they presented with bone marrow infiltration with or without detectable involvement of peripheral blood but without splenomegaly and with apparently no other extranodal or nodal involved site. Results. Incidence was not significantly different according to sex (male: 47; female: 53%), median age at diagnosis was 68 years (20–94 years); 244 pts (65%) had stage III-IV disease. LDH was elevated in 45/212 (21%) tested pts, beta2-microglobulin in 108/205 (53%) tested pts. B symptoms were reported in 27/368 pts (7%). Five percent of pts had an ECOG performance status higher than 1. Serologic evidence of hepatitis C virus (HCV) infection was reported in 45/243 (19%) pts for whom the data was available. Among the 186 MALT lymphomas, 91 pts (49%) had a gastric localization, and 54 (29%) had multiple extranodal sites of disease involvement. Median overall survival (OS) and progression-free survival of the whole population were 15 years and 8 years, respectively. After a median follow-up of 5 years, HT was observed in 14 cases (4%, 95%CI:2%-6%). A diagnosis of diffuse large B cell lymphoma was documented in 12 pts (85.7% of patients undergoing HT), while in two cases the diagnosis was of classical Hodgkin lymphoma and mantle cell lymphoma, respectively. HT occurred after a median interval of 3 years (range: 1–12 years) after diagnosis. With respect to MZL type, HT occurred in 6% SMZL, 4% MALT lymphomas, 3% NMZL, and 2% uMZL (P=0.635). Risk of HT was 4% (95%CI, 2–8%) at 5 years, 6% (95%CI:3%-11%) at 10 years and 9% (95%CI, 5–16%) at 15 years; the rate of transformation tended to plateau from that point onward. At the time of HT, most pts had high LDH serum levels (8/11, 73%) and presence of B symptoms (6/10, 60%). After transformation, nine pts received anthracycline-containing regimens, and four pts were treated with high dose cytarabine regimens; in a single patient only supportive measures were adopted. In four pts, autologous stem cell transplantation was performed after induction. At a median follow-up of 12 months after HT, five of 14 pts died, all for lymphoma-related causes, with a 2-year post-transformation survival rate of 38% (95%CI:5%-74%). There was no significant association between the risk of HT and any of the clinical variables at diagnosis or frontline treatment strategies. Conclusions. This large retrospective series documents that the risk of HT is low across all MZL types. The incidence of HT in MZL is apparently lower than that of other indolent B cell malignancies, namely follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). As also observed in FL and CLL, HT in MZL occurs relatively early during the clinical course, pointing to putative biological differences at diagnosis in MZL patients destined to transform. Disclosures: Off Label Use: Trial partially supported by a research grant by Celgene. Lenalidomide was provided free by Celgene. The use of Lenalidomide is off-label in untreated DLBCL. Bertoni:OncoEthix SA: Research Funding.

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Nandagopal, Lakshminarayanan, J. Christine Ye, Marie Ventimiglia, Muneer H. Abidi, Lois Ayash, Jeffrey Zonder, Lawrence G. Lum, et al. "Influence of Race on Outcomes in Multiple Myeloma Patients with Renal Dysfunction Undergoing High Dose Therapy Followed By Autologous Stem Cell Transplant." Blood 124, no. 21 (December 6, 2014): 5904. http://dx.doi.org/10.1182/blood.v124.21.5904.5904.

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Abstract Approximately 20% of Multiple Myeloma (MM) patients (pts) have renal dysfunction(RD) at the time of diagnosis and some more may develop it during the course of their disease. Autologous stem cell transplant (ASCT) is a treatment modality for this incurable malignancy and there are ongoing studies to determine the optimal timing of ASCT in this disease. There are conflicting data regarding the outcomes among different racial groups with regards to ASCT in MM. In this restrospective review we studied outcomes in pts of different races with RD undergoing ASCT for MM. Between June 2005 and December 2013, we identified 107 pts with MM with RD (creatinine clearance < 60 ml/min/1.73 m2) who were not on hemodialysis and underwent ASCT at our institution. Of the 107 pts, 76 were caucasian(C) pts and 31 were identified as other (O) races (25 African American, one Hispanic, two Middle-eastern, three Asian). The patient characteristics of both groups are shown in Table 1. There were no statistically significant differences in the characteristics between the 2 groups. Approximately a quarter of the pts received their melphalan dose on the inpatient unit in both groups. During the hospitalization all pts received G-CSF from Day +6 till absolute neutrophil count ≥ 1500/µl and antimicrobial prophylaxis with norfloxacin, acyclovir and fluconazole. The median follow up was 35.9 months (range, 5.1-106.3). One patient in the C group died 98 days after ASCT and had evidence of disease progression. There were no deaths in the O group during the 100 days after ASCT. Table 2 shows post ASCT disease status and details about post ASCT maintenance therapy. There were no statistically significant differences between the groups in disease status or change in disease status at day 100 post ASCT. Although more patients in the C group received maintenance therapy post ASCT, this difference was not statistically significant. Figures 1 and 2 show the relapse free survival (RFS)and overall survival (OS) of both groups. The median RFS for C and O groups were 32.3 and 20.9 months (p =0.63, log rank), respectively. The median OS of the C and O groups were 73.1 and 47.8 month (p=0.31, log rank), respectively. Our limited experience suggests that there was no effect of race in the post ASCT outcomes for MM pts with RD. ASCT was safe with acceptable transplant related mortality and good long -term outcomes for MM pts with renal dysfunction. Table 1: Patient Characteristics (N=107) Patient Characteristics Caucasians (n=76) Others (n=31) Median Age (range) 63 (36-73) 64(28-73) 0.58 Gender Male 42 (55%) 17 (55%) 0.9 Females 35 (45%) 14 (45%) Chemo regimens prior to ASCT 1 51 (67%) 21 (68%) 0.95 ≥ 2 25 (33%) 10 (32%) Agents used prior to ASCT IMid 12 (16%) 4 (13%) 0.85 PI 18 (24%) 9 (29%) Both 46 (60%) 18 (58%) Disease status at time of ASCT PD 7 (10%) 5 (16%) 0.35 SD 9 (12%) 4 (13%) PR 20 (26%) 11 (35%) VGPR 20 (26%) 8 (26%) CR 20 (26%) 3 (10%) Median creatinine clearance (range) 45.5 (15-60) 43 (21-60) 0.35 Subtype* IgG Kappa 29 (34%) 18 (58%) 0.25 IgG Lambda 18 (24%) 6 (19%) Ig A Kappa 9 (12%) 2 (6%) Ig A Lambda 5 (7%) 3 (10%) K Light Chain 6 (8%) 0 L Light Chain 5 (7%) 0 Non- Secretory 3 (4%) 2 (6%) Cytogenetic Risk Standard 65 (85%) 18 (58%) 0.67 High Risk 5 (7%) 2 (6%) Median Melphalan Dose mg/m2 (range) 140 (140-200) {140(58),160(5), 180(4),200(9)}® 140 (100-200) {100(2),140(25), 200(9)} 0.89 Administration of Melphalan Inpatient 18 (24%) 9 (29%) 0.56 Outpatient 58 (76%) 22 (71%) Median CD 34 Cell dose x106/kg (range) 3.3 (2 -10.1) 3.9 (2.3-9.5) 0.34 Median Engraftment Day (range) Neutrophil 12 (11-20) 12(10-27) 0.86 Platelets 18(11-88) 17 (11-42) 0.10 Median Days of Hospitalization (range) 15 (9-65) 16 (12-55) 0.96 * 1 pt each in the caucasian group had IgD Lambda and IgM Kappa paraprotein ® Pts received 160 and 180 mg doses as part of a study PI: proteosome inhibitors, PD: progressive disease, SD: stable disease, PR: partial response, VGPR: very good partial response, CR: Complete response Table 2: Disease status at Day 100 post ASCT Caucasian (N=76) Other (N=31) P Value Disease Status CR 26 (34%) 6 (19%) 0.5 VGPR 20 (26%) 12 (38%) PR 17 (22%) 6 (19%) SD 7 (9%) 4 (13%) PD 2 (3%) 2 (7%) Not available 4 (6%) 1 (3%) Change in Disease Status Improved 23 (30%) 13 (42%) 0.66 Unchanged 45 (59%) 15 (48%) Worsened 4 (6%) 2 (7%) Not available 4 (6%) 1 (3%) Maintenance Therapy IMid 40 (53%) 9 (29%) 0.15 PI 2 (3%) 1 (3%) None 29 (38%) 19 (61%) Not Known 5 (7%) 2 (7%) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Ruutu, Tapani, Liisa Volin, Dietrich W. Beelen, Rudolf Trenschel, Juergen Finke, Marc Schnitzler, Jerzy Holowiecki, et al. "Reduced Toxicity Conditioning with Treosulfan and Fludarabine in Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndromes: Results of an International Prospective Phase II Trial." Blood 112, no. 11 (November 16, 2008): 3274. http://dx.doi.org/10.1182/blood.v112.11.3274.3274.

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Abstract Recent preclinical and clinical data have revealed treosulfan a promising alternative conditioning agent for allogeneic hematopoietic stem cell transplantation. After previous dose-finding studies in high-risk patients suffering from various hematological malignancies this prospective, multicenter phase II trial was carried out to assess the safety and efficacy of treosulfan-based conditioning in MDS patients. Eleven centers from four countries participated. Forty-five patients (24 females, 21 males) with a median age of 50 years (range 22 – 63 years) were included. In 33 % of the transplantations the donor was related (MRD), in 67 % unrelated (MUD). Forty-seven per cent of the patients had received some kind of treatment before the transplantation, including 13 % given AML-like induction therapy. The IPSS risk groups were: 7 % “low”, 44 % “Int-1”, 31 % “Int-2” and 18 % “high”. At the time of transplantation 44 % of the patients had 5 % or more blasts in the bone marrow. In total, 9 % of all patients were considered non-eligible to standard conditioning therapy because of comorbidity or age. Treosulfan (14 g/m2, 2 hour infusion) was administered on days -6 to -4 and fludarabine (30 mg/m2, 30 min infusion) on days -6 to -2. The graft was peripheral blood stem cells in 89 % and bone marrow in 11 % of the transplantations. GvHD prophylaxis consisted of ciclosporine-A and a short course of MTX as well as ATG-Fresenius® (10 mg/m2 i.v., days -4 to -2) in case of MUD. This analysis is based on a median follow-up of 15 months (range 3.3 – 35.8 months). The conditional cumulative incidence (CI) of neutrophil (> 0.5 x 109/l), leukocyte (>1 x 109/l) and platelet (> 20 x 109/l) engraftment reached 91 %, 93 % and 89 % on day +28 and 98%, 98 % and 91 % overall, respectively. The median time to engraftment was 18, 17 and 17 days, respectively (G-CSF treatment was not recommended in the protocol). The CI of complete donor chimerism increased from 73 % (day +28) to 93 % (day +100). The frequencies (exceeding 5 %) of adverse events CTC grade III/IV with at least possible relatedness to the study drug and occurring during 28 days post-transplantation were 13 % for CTC category “gastrointestinal” and 24 % for “infection”. Frequencies for grade III/IV hyperbilirubinemia, mucositis/stomatitis and seizures were low (13 %, 2 % and 0 %, respectively). There were two cases of mild VOD which resolved before day +20 after the transplantation. The CI of grade II - IV acute GvHD was 24 % and that of grade III-IV 16 %. The CI of chronic GvHD at 1 year was 45 % and that of extensive cGvHD 25 %. The CI of non-relapse mortality was 9 % at 100 days and 15 % at 1 year, and that of relapse/progression 14 % at 1 year. The Kaplan-Meier estimates of OS and DFS at 1 year were 80 % and 71 %. These interim phase II data confirm promising safety and efficacy of this alternative treosulfan-based conditioning therapy in MDS patients, as previously reported for AML and CML patients by others. Final survival data with 1-year follow-up for all living patients will be available in September 2008. These encouraging results give a base for future trials comparing treosulfan/fludarabine conditioning with conventional conditioning regimens.

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Dacosta Byfield, Stacey, Nicole Engel-Nitz, Timothy Bancroft, Amy J. Anderson, Carolina Reyes, Arliene Ravelo, Sarika Ogale, May Chen, and Matthew J. Matasar. "Differences in Patients with Progressive Versus Non-Progressive AML, CLL, or NHL: Implications for Proposed Bundled Payment Strategies." Blood 126, no. 23 (December 3, 2015): 4528. http://dx.doi.org/10.1182/blood.v126.23.4528.4528.

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Abstract Background: Increasingly, payers are redefining how payments for cancer care are structured. Demonstration programs and policy proposals by insurers and oncology organizations have bundled payments for various services, including chemotherapy. The impact of such payment policies may vary for patients (pts) with hematologic malignancies given their widely varying disease severity. Progression of disease (PD), and costs associated with it, may stress bundled payment programs, particularly if such programs do not accurately assess risk of progression across the insured cohort. To inform this ongoing development of new payment strategies for pts with hematologic malignancy, this study compared patterns of care in pts with AML, CLL or other forms of NHL who do, or do not, experience PD. Methods: This retrospective studyused medical and pharmacy claims from a large national US health plan to identify commercially insured and Medicare Advantage (MA) pts age ≥18 years from 1/2007 - 8/2014 with ≥2 medical claims for AML (ICD-9-CM code 205.0x), CLL ( ICD-9-CM code 204.1x), or other NHL (ICD-9-CM codes 200.xx, 202.0x-202.2x, 202.4x, 202.7x-202.9x, 203.8x, 204.8x-204.9x, 273.3x). Pts required ≥1 claim for systemic anti-cancer therapy (SACT); the first observed claim was the index date. Continuous enrollment (CE) in the health plan for 6 months (mths) prior to (baseline period) and ≥6 mths after index date (variable follow-up period) was required; pts with <6 mths of follow-up due to death were included. Pts with baseline SACT or additional primary malignancies were excluded. Line of therapy (LOT) periods were defined. The 1st LOT (LOT1) started on index date; regimens included all drugs received in the first 45 days. LOT1 ended at the earliest of: start of a new drug, ≥60-day gap in initial regimen, death or end of CE or study period. LOT2 started with a SACT after LOT1 end. PD was defined as: start of LOT2, receipt of hospice care (based on procedure or revenue codes) or death (based on Social Security Administration death data). Results: Among 667 AML, 1354 CLL and 9399 NHL pts who met study criteria, 70%, 45%, and 46% respectively had PD during the study period. Mean (median) time in mths to PD was 6.6 (4.2) for AML, 12.8 (9.2) for CLL and 10.0 (7.1) for NHL. Descriptive results are shown in the Table. Compared to pts without PD during the study period, pts who progressed were MA pts, older and had shorter initial LOTs. The most common initial therapy varied across PD cohorts. Among pts with PD, the AML cohort had the highest percentage of death and evidence of hospice care. Conclusion: Characteristics and treatment patterns varied for pts with PD versus non-PD AML, CLL and NHL. Understanding the variability across patient groups will aid in the development of new bundled payment policies and help providers determine whether and in which payment systems to participate. Table 1. AML CLL NHL PD N=464 No PD N=203 PD N=604 No PD N=750 PD N=4291 No PD N=5108 Age, yrs mean (SD), median^# 60 (17), 62 58 (17), 59 71 (11), 72 67 (11), 67 64 (14), 65 60 (16), 62 Baseline Quan-Charlson comorbidity score mean (SD), median# 3.1 (1.6), 2 3.1 (1.6), 2 2.8 (1.3), 2 2.7 (1.2), 2 3.4 (2.0), 3 3.3 (1.9), 2 Male, N (%)# 271 (58) 115 (57) 366 (61) 490 (65) 2480 (58) 2832 (55) Insurance, N (%)*^# Commercial 300 (65) 148 (73) 284 (47) 428 (57) 2,723 (63) 3489 (68) MA 164 (35) 55 (27) 320 (53) 322 (43) 1568 (37) 1619 (32) Stem Cell Transplant, N (%) 105 (23) 61 (30) 11 (2) 5 (1) 443 (10) 169 (3) Length of follow-up, mths, mean (SD), median ^# 17.6 (17.1), 12.1 19.9 (15.5), 14.4 28.6 (21.4), 23.7 22.4 (15.9), 17.2 28.2 (21.5), 22.3 27.2 (19.9), 20.9 Length of LOT1, mths, mean (SD), median *^# 3.8 (4.3), 2.5 5.4 (6.5), 3.5 3.6 (4.0), 2.8 4.8 (4.0), 4.3 4.1 (3.6), 3.6 5.2 (5.1), 4.5 Monotherapy in LOT1*^# 322 (69) 158 (78) 371 (61) 272 (36) 1623 (38) 1254 (25) Biologic in LOT*^# 136 (29) 38 (19) 384 (64) 603 (80) 3523 (82) 4066 (80) Most common LOT1 regimens (%)┼ 1st aza (19) cyt (17) R (24) FCR (23) R (26) RCHOP (39) 2nd dec (15) dec (17) chl (19) BR (21) RCHOP (25) R (14) 3rd cyt (9) aza (17) FCR (12) R (16) RCVP (9) BR (7) Hospice, N (%) 124 (27) - 74 (12) - 664 (15) - Died, N (%) 204 (44) - 177 (29) - 1040 (24) - *^# p<0.05 for AML, CLL and NHL progression cohorts respectively ┼no testing Aza-azacitadine, B-bendamustine, C-cyclophosphamide, chl-chlorambucil, cyt-cytarabine, dec-decitabine, F-fludarabine, R-rituximab, V-vincristine RCHOP=R,C,V,doxorubicin±prednisone RCVP=R,C,V±prednisone Disclosures Dacosta Byfield: Optum: Employment. Engel-Nitz:United Health Group: Equity Ownership; Optum: Employment. Bancroft:Optum: Employment; United Health Group: Equity Ownership. Anderson:Optum: Employment; United Helath Group: Equity Ownership. Reyes:Genentech: Employment; Roche: Equity Ownership. Ravelo:Roche: Equity Ownership; Genentech, Inc.: Employment. Ogale:Roche: Equity Ownership; Genentech, Inc.: Employment.

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Yassin, Mohamed A., Ali Taher, Vikram Mathews, Hsin-An Hou, Tahir Shamsi, Tulin Tuglular, Zhijian Xiao, et al. "Myeloproliferative Neoplasms in Asia, Including Middle East, Turkey, and Algeria: Epidemiological Indices and Treatment Practice Patterns from the Multinational, Multicenter, Observational MERGE Registry." Blood 132, Supplement 1 (November 29, 2018): 5461. http://dx.doi.org/10.1182/blood-2018-99-114416.

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Abstract Background The Philadelphia chromosome−negative classical myeloproliferative neoplasms ([MPNs], including essential thrombocythemia [ET], polycythemia vera [PV], and myelofibrosis [MF]), are generally associated with a substantial disease burden, often leading to a reduced quality of life (QOL) and shortened survival in many patients (pts). There has been a lack of estimates for the incidence/prevalence and treatment patterns of MPNs in many regions of the world, including countries from South Asia, Asia Pacific, Middle East, and Turkey. Hence, there is a need to establish databases like registries, which would provide information on the "real-world" data in these regions. The MERGE registry was initiated with an objective to collect data on the epidemiological indices of MPNs and existing treatment patterns in Asia, including Middle East, Turkey, and Algeria. This primary descriptive analysis from the MERGE registry was performed to estimate the incidence/prevalence, natural disease course, and treatment patterns of MPNs in these countries. Methods MERGE is a multinational, multicenter, nonintervention study that included adult pts with MPNs, who were diagnosed according to World Health Organization 2008 criteria. The data were collected retrospectively (since diagnosis) and prospectively after enrollment in the study. Disease assessments were scheduled every 6 months up to 5 visits, with a minimum of 2 years of follow-up. Pts who participated or were participating in a randomized clinical trial were allowed. Data were analyzed descriptively. Results In total, 884 MPN pts (ET=373, PV=301, MF=169, and unclassified=41) were included in the full analysis data set. The median age was 58 years (range, 47-66 years; younger compared to other regions) and 50% pts were males. Baseline pt characteristics by MPN subtype are summarized in Table 1. About 57% of pts were diagnosed by incidental finding of abnormal blood results followed by bone marrow evaluation. In these countries, the prevalence and incidence of MPNs are estimated to be 57-81 and 12-15 per 100.000 hospital-patients per year over the last 4 years, respectively. As assessed by MPN Symptom Assessment Form (MPNSAF), 92% of the pts reported at least 1 symptom. At baseline, fatigue was the most common symptom in all 3 MPN subtypes (71% MPN; 78% MF; 71% ET; and 68% PV). Inactivity (64%), early satiety (61%), abdominal discomfort (57%), bone pain (56%), weight loss (52%), night sweats (46%), and fever (29%) were more common in MF; whereas, itching in PV pts (50%). MF pts had the highest total symptom score at baseline (mean [SD], 23.5 [17.47]) as compared to ET (mean [SD], 14.6 [14.26]) and PV pts (mean [SD], 16.6 [14.84]). Overall, 64% of pts had ECOG performance status of 0 and 26% had ECOG 1. During study period, the most common nonpharmacological intervention was red cell transfusion in MF and ET pts, and phlebotomy in PV pts. Splenectomy (n=2) and stem cell transplantation (n=4) were rarely employed (6 MF pts). Hydroxyurea (HU) was the most common first-line therapy in all 3 MPN subtypes (overall, 54%; PV, 61%; ET, 54%; and MF, 39%), followed by aspirin. Other common first-line therapies were anagrelide (10%) and interferon (9%) in ET pts, antineoplastic (6%) and clopidogrel (6%) in PV, and JAK2 inhibitors in MF pts (15%). More than 75% of the induction therapies were monotherapies, with less than 3% of pts receiving 3 or more drug combinations as primary treatment. Patients with MF often received monotherapy (81%), than the other patients with MPN. Median duration of first-line therapy was about 6 months (95% CI, 1-21 months), and first-line therapy discontinuation rates of 35%, 36%, and 30% were noted in ET, PV and MF pts, respectively. Interferon was used in 8% of in the second-line setting. JAK2 inhibitors were more frequently (14%-17%) used in the second-and third-line settings. Conclusions The prevalence and incidence of MPNs in countries from Asia Pacific were derived using the number of pts visiting the corresponding hospitals. Thus, the resulting incidence and prevalence reported here are not directly comparable with the country-based prevalence/incidence and may overestimate the actual values. At baseline, pts with MPNs had significant disease burden. The most common first-line therapy was HU, though discontinuation rates of first-line therapies were high, and JAK2 inhibitors were mostly used in the second-line/third-line settings. Disclosures Yassin: Novartis: Research Funding. Taher:La Jolla Pharmaceutical: Research Funding; Ionis Pharmaceuticals: Consultancy; Celgene Corp.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Protagonist Therapeutics: Consultancy. Kim:Novartis Korea: Honoraria. Rippin:Employee of IQVIA - doing consultancy for Novartis: Consultancy. Sadek:Novartis Pharmaceutical Corporation: Employment. Siddiqui:Novartis Pharma AG: Employment, Equity Ownership. Wong:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Varettoni, Marzia, Gian Matteo Pica, Federica Cocito, Silvia Mangiacavalli, Cristiana Pascutto, Mario Lazzarino, and Alessandro Corso. "Changing Pattern of Presentation in Monoclonal Gammopathy of Undetermined Significance: A Study on 1400 Cases." Blood 112, no. 11 (November 16, 2008): 2706. http://dx.doi.org/10.1182/blood.v112.11.2706.2706.

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Abstract Background. Monoclonal gammopathy of undetermined significance (MGUS) is defined by the presence of a serum M-protein <3 g/dL, bone marrow plasma cells (BMPC) <10% and absence of end-organ damage. The risk of malignant transformation is 1% per year. Size and type of M-protein and an abnormal serum free-light chains (FLC) ratio at diagnosis are reported as the main risk factors for transformation. Aims of the study. To evaluate whether the pattern of presentation of MGUS has changed over the last three decades. Patients and methods. The charts of MGUS patients (pts) diagnosed from 1975 to 2007 were reviewed. The following data were gathered: age, sex, haemoglobin (Hgb), type and size of serum M-protein, uninvolved Ig levels, serum FLC, urine M-protein, BMPC, serum albumin and β2-microglobulin. The study included 1400 pts divided into three groups according to the date of diagnosis: 1975–1987 (group I, 102); 1988–1997 (group II, 380); 1998–2007 (group III, 918). Differences among groups were evaluated using chi-square test for categorical variables and Kruskal-Wallis non-parametric Anova for numerical variables. A P-value ≤0.05 was considered statistically significant. Results., The median age of patients was 63 years (range 20–92), 740 were males and 660 females. The median time from the first detection of M-protein to diagnosis of MGUS was 3.2 months (range 1–264). Serum M-protein was 73% IgG, 13% IgM, 11% IgA, 3% biclonal; light chain was k in 63% of pts, λ in 37%. The serum M-protein was <1 g/dL in 284 patients (21%), 1–1.5 g/dL in 502 (36%), 1.5–2 g/dL in 373 (27%) and ≥2 g/dL in 216 (16%). M-protein size was not reported in 25 cases. The median levels of uninvolved IgG, IgM and IgA were 1350 mg/dL (range 110–7460), 94 mg/dL (range 40–4680) and 162 mg/dL (range 22–2370) respectively. In 236 evaluable pts, median levels of serum FLC k and λ were 17.1 mg/L (range: 1.4–423) and 17.3 mg/L (range: 2–299). Urine M-protein was detected in 19% of pts with a median level of 23.8 mg/L (range 4–450). The median BMPC percentage was 5 (range: 1–10). The median values of Hgb, serum albumin and β2-microglobulin were 14 g/dL (range: 8.6–19.7), 4.3 g/dL (range 2.5–6) and 1930 mcg/L (range 865–44300) respectively. The comparison among the three groups showed statistically significant reduction of serum M-protein levels (p<0.0001), BMPC (p<0.0001), β2-microglobulin (p=0.0001) and increase of Hgb (p<0.0001) and albumin (p=0.0001) over time. In particular, the proportion of pts with a serum M-protein <1 g/dL increased from 4% in group I to 12% in group II and to 26% in group III. A serum M-protein ≥2 g/dL was present in 35%, 22%, 11% of pts in the three groups respectively (p<0.0001). With a median follow-up was 40 months (range: 3–396), corresponding to 7577 person-year, the cumulative probability of malignant transformation was 9%, 18%, 28% at 5, 10, 15 years respectively. Group III pts had a significantly lower 5-year probability of transformation (5%) as compared to groups I and II (20% and 11% respectively). Conclusions. The pattern of presentation of MGUS has changed over time. Patients diagnosed in the last decade have more favourable presenting features as compared to those diagnosed before. This could be due to the availability of more sensitive diagnostic techniques able to detect minimal M-proteins. Another possible explanation is that pts are more frequently and promptly referred by their treating physicians to an hematologic centre, allowing an earlier diagnosis. Both circumstances could led to the identification of a subset of pts with different presentation and maybe a better outcome with respect to the MGUS diagnosed in the past decades. This could entail a different approach of physicians in the management of MGUS patients.

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Walter, Roland B., Sarah A. Buckley, John M. Pagel, Brent L. Wood, Ted A. Gooley, Brenda M. Sandmaier, Min Fang, et al. "Quantitative Significance of Minimal Residual Disease Before Myeloablative Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia in First and Second Complete Remission." Blood 120, no. 21 (November 16, 2012): 655. http://dx.doi.org/10.1182/blood.v120.21.655.655.

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Abstract Abstract 655 Background: Minimal residual disease (MRD), detectable by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT), is associated with increased relapse and lower disease-free survival (DFS) and overall survival (OS) in acute myeloid leukemia (AML) in first complete remission (CR1). As the relationship between MRD and outcome is less studied for patients in second CR (CR2), we assessed whether this association is similar to that seen in CR1 patients, and examined the impact of MRD levels on outcome. Patients and Methods: We studied 253 consecutive patients (median age: 43.1 [range: 0.6–72.6] years) receiving myeloablative HCT for AML in first (n=183) or second (n=70) CR or CR with incomplete blood count recovery (CRi) between May 2006 and November 2011. Pre-HCT bone marrow aspirates were obtained in all patients and analyzed by routine karyotyping and ten-color MFC. MRD was identified as a cell population showing deviation from normal antigen expression patterns as compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Data are current as of August 6, 2012. Results: Before HCT, 85.7% of patients met morphological criteria for CR, whereas 14.3% had CRi. Thirty-six (19.7%) patients in CR1 and 18 (25.7%) patients in CR2 had MRD (MRDpos) as determined by MFC, with median of 0.29% (range: 0.007–7.8%) and 0.41% (0.05–3.5%) abnormal blasts for MRDpos CR1 and CR2 patients. Among CR1 patients, the 3-year estimates of OS where 73% (64–80%) and 27% (10–47%) for MRDneg and MRDpos patients, respectively; among CR2 patients, 3-year OS was estimated to be 71% (55–82%) and 47% (23–69%), respectively (Figure 1). Three-year estimates of relapse among CR1 patients were 21% (14–28%) and 59% (41–73%), respectively, and 20% (9–32%) and 68% (37–86%), respectively, among CR2 patients. This relatively similar outcome for CR1 and CR2 patients may be at least partly accounted for by more favorable cytogenetic risk profile of the leukemias in patients transplanted in CR2 (favorable-risk: 22.9% vs. 3.3%; adverse-risk leukemias: 11.4% vs. 26.2%; secondary AML: 8.6% vs. 34.4%). The risk of death for patients who were MRDpos was 3.27-times that among patients who were MRDneg (95% CI, 2.11–5.05; p<0.0001), and the risk of relapse was also increased (hazard ratio [HR]=5.46 [3.39–8.81], p<0.0001). The association of MRD with outcome among patients in CR1 is similar to that among patients in CR2 (p=0.46, p=0.48 tests of interaction for mortality, relapse). If MRD was modeled as a continuous linear variable, both the risk of death and the risk of relapse increased as MRD increased (p=0.001, p<0.0001). Categorizing MRD levels as 0 (n=199), 0.1% or less (n=14), >0.1–1% (n=24), and >1% (n=16), the risk of death increased with each increasing level of MRD relative to the MRDneg group (Figure 2), but the magnitude was fairly similar across all MRDpos groups (HR=2.69, HR=2.96, HR=4.41), and the lowest level of MRD (0.1% or less) was not statistically significantly different from the highest level of MRD (>1%, p=0.30). Similarly, the risks of death in the three MRDpos groups relative to the MRDneg group were HR=5.24, HR=4.32, and HR=8.67, and the difference between the groups with the lowest and highest levels of MRD were not statistically significant (p=0.28). Adjustment for cytogenetic risk, CR duration, pre-HCT karyotype, pre-HCT blood count recovery, and the HCT preparative regimen led to the same qualitative results. Conclusion: The negative impact of MRD on outcome among AML patients in CR2 is similar to the negative impact seen in patients in CR1. Our data indicate that outcomes of MRDneg AML patients are excellent after myeloablative HCT in either CR1 or CR2. Even patients with minute amounts of MRD (0.1% or less) have significantly worse outcomes than MRDneg patients. Patients with higher levels of MRD (>1%) had worse outcome than those with minute amounts, but the limited number of MRDpos patients limit the power to detect statistically significant differences between these groups. The poor outcome of MRDpos patients provides the rationale for studies investigating whether cure rates could be improved by MRD-directed therapy before, during, or after HCT. Disclosures: No relevant conflicts of interest to declare.

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Arnan, Montserrat, Rosa Coll, Mar Tormo, José María Bastida, María Calbacho, Teresa Bernal, Fernando Ramos, et al. "Impact of Treatment on Overall Survival (OS) in Higher-Risk Myelodysplastic Syndromes (MDS): A Report from the Erasme Study." Blood 126, no. 23 (December 3, 2015): 5240. http://dx.doi.org/10.1182/blood.v126.23.5240.5240.

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Abstract Introduction: Treatment of MDS has undergone a dramatic change in recent years with the emergence of demethylating agents; however, there are limited data on the impact of these agents on OS in the "real-world" setting. The aim of this study is to evaluate the use and outcomes of different therapies in patients (pts) with International Prognostic Scoring System (IPSS)-defined Intermediate-2- and High-risk (higher-risk) MDS. Methods: The ERASME study (CEL-SMD-2012-01) is an observational, prospective study of pts with either MDS or chronic myelomonocytic leukemia (CMML); pts were defined using the 2008 World Health Organization (WHO) classification system. Initial pt management strategy was classified into 3 groups: active therapy (AT), such as chemotherapy or treatment with azacitidine (AZA), lenalidomide (LEN), etc.; allogeneic hematopoietic cell transplantation (HCT), which included those pts receiving other therapies before transplantation; and observation and support (OB&SP), which included red blood cell and platelet transfusions, and growth factors. OS rates of higher-risk pts are presented using the Kaplan-Meier method. Results: A total of 160 pts with higher-risk MDS were recruited between Jan 2013 and Feb 2015. Median follow-up was 8.6 months (interquartile range [IQR] 4.0-11.8). Pt characteristics are described in the Table. AT was the first therapeutic decision in 83 (52%) pts, HCT in 43 (27%), and OB&SP in 34 (21%). Within the AT group, 75 (90%) pts received AZA alone, 5 (6%) AZA plus chemotherapy, and 3 (4%) received other options; most pts (n = 78; 94%) were treated with a 7-day regimen. Among the 43 potential HCT candidates, 40 (93%) had received prior therapy: 25 (58%) with AZA alone, 8 (19%) with chemotherapy, 6 (14%) with AZA plus chemotherapy, and 1 (2%) with LEN; 3 (7%) had not received prior therapy. Of the potential HCT candidates, 20 had undergone transplantation within a median of 8 months (IQR 4.1-13.3); 7 (16%) pts died before transplantation and 16 (37%) are still awaiting transplantation. The main reasons for OB&SP being the initial pt strategy were disease risk (100%), age (95%), comorbidities (60%), and symptomatology (44%). At last follow-up, 70 of 160 pts (44%) had died after a median of 6 months (IQR 2.9-11.8): 34 (41%), 14 (32%), and 22 (65%) pts undergoing AT, HCT, and OB&SP, respectively (log-rank 6.9; P = 0.032). Median OS in pts who received AT, HCT, and OB&SP was 18.60 months (95% confidence interval [CI] 13.1-21.8), 14.92 months (95% CI 11.6-not reached), and 8.44 months (95% CI 4.3-13.4), respectively. Median OS was significantly longer in the AT group compared with the OB&SP group (hazard ratio [HR] 1.9; 95% CI 1.1-3.3; P = 0.0197). No statistically significant difference was observed in OS between pts treated with AT and those considered potential HCT candidates (HR 0.9; 95% CI 0.5-17.7; P = 0.8). Conclusions: The preliminary data from this observational, prospective study indicate that AT significantly prolongs OS compared with OB&SP when treating pts with higher-risk MDS in a real-world setting. AZA was the most common treatment in the AT group. Abstract presented on behalf of the ERASME Study Investigators Group. Table. Baseline characteristics of the MDS population (N = 160) Characteristic Age, median (IQR), years 73 (64.5-79.0) Male, n (%) 86 (53.8) Bone marrow blast count, median (IQR), % 12 (7.5-16.3) Hemoglobin level, median (IQR), g/dL 9.55 (8.0-10.6) Platelet count, median (IQR), × 109/L 64.75 (41.0-121.0) ANC, median (IQR), × 109/L 1 (0.47-2.20) Cytogenetic risk (by IPSS-R), n (%) Low 64 (40.0) Intermediate 9 (5.6) High 27 (16.9) Very High 39 (24.4) Missing data 21 (13.1) WHO classification, n (%) RCMD 17 (10.6) RAEB type 1 28 (17.5) RAEB type 2 94 (58.8) Unclassified 2 (1.3) Missing 1 (0.6) AML 20-30% blasts 18 (11.3) IPSS risk classification, n (%) Intermediate-2 86 (53.8) High 71 (44.4) Missing 3 (1.9) IPSS-R risk classification, n (%) Very Low 4 (2.5) Low 28 (17.5) Intermediate 20 (12.5) High 40 (25.0) Very High 46 (28.8) Missing 22 (13.8) AML, acute myeloid leukemia; ANC, absolute neutrophil count; FAB, French-American-British; IPSS-R, Revised-IPSS; RAEB, refractory anemia with excess blasts; RCMD, refractory anemia with multilineage dysplasia. Disclosures Off Label Use: Azacitidine was used to treat patients who are potential hematopoietic stem cell transplant candidates. Ramos:GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria. Rafel:Celgene Corporation: Employment. Valcárcel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Perry, Ashley M., Tao Zou, Andrew M. Brunner, Donna S. Neuberg, and Amir T. Fathi. "The Impact of Insurance Status at Diagnosis on Overall Survival in Chronic Myeloid Leukemia: A Population-Based Analysis." Blood 126, no. 23 (December 3, 2015): 631. http://dx.doi.org/10.1182/blood.v126.23.631.631.

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Abstract Introduction: Survival among patients diagnosed with chronic myeloid leukemia (CML) has markedly improved with the advent of tyrosine kinase inhibitors. Nonetheless, access to care, including medication cost and adherence, may be barriers to therapeutic effectiveness. We performed a population-based analysis to determine if insurance status at the time of CML diagnosis influenced patient outcomes. Methods: We used the Surveillance, Epidemiology, and End Results Program (SEER) database (November 2014 submission) to identify patients age 15 or older, diagnosed with CML between 2007 and 2012 (SEER ICD-O3 recodes 9863 and 9875). We included patients with documented insurance status at diagnosis and categorized them as either private insurance, Medicaid coverage, or uninsured. We excluded patients with unknown insurance status at diagnosis. The primary outcome was overall survival according to insurance status. We performed a stratified analysis looking at patients age 15-64 and patients 65 or older; we did not include uninsured patients over age 65 in the analysis (n=16) due to Medicare eligibility. Covariates of interest in multivariable analysis included age at diagnosis, race, ethnicity, sex, and marital status at diagnosis. Overall survival was compared by log-rank test and estimated by the method of Kaplan and Meier. P-values were significant to the 2-sided 0.05 level. Results: 5784 patientswere diagnosed with CML between 2007 and 2012 and had insurance status documented at diagnosis. Of patients age 15-64, uninsured and Medicaid patients were younger, more often non-white race and Hispanic ethnicity, and less often married (Table 1). Over age 65, Medicaid patients were more often female, non-white race and Hispanic ethnicity, and less often married. Median follow up was 32 months. Among patients age 15 to 64, being uninsured or having Medicaid was associated with worse survival compared to insured patients (5-year OS uninsured 72.7%, Medicaid 73.1%, insured 86.6%, p<0.0001) (Figure 1A). For patients over age 65, there was no difference in 5-year OS between patients with Medicaid and those with other insurance (40.2% vs. 43.4%, p=0.0802). In multivariable analysis of patients age 15-64, compared to insured patients, there was increased mortality among patients who were uninsured (HR 2.156, p<0.0001) or on Medicaid (HR 1.972, p<0.0001). There was worse survival with increased age (HR 1.046 per year, p<0.0001), male sex (HR 1.282, p=0.0279) and, compared to married persons, being single (HR 1.883, p<0.0001). For patients over age 65 at diagnosis, only age was associated with increased mortality (HR 1.078 per year, p<0.0001). Conclusions: CML patients under age 65 without insurance or with Medicaid had significantly worse survival compared to patients with insurance. This difference was not noted with patients over age 65; whose survival was relatively poorer regardless of insurance status, as previously described (Cancer 2013;119:2620). Marital status and race/ethnicity also impacted survival. Despite highly effective therapies currently available for CML, these findings suggest that many patients may not have access to or receive appropriate care, in part related to insurance coverage. Table 1. Patient Demographics Age 15-64 p-value Age 65+ p-value (3626 patients) (2142 patients) Uninsured Medicaid Insured Medicaid Insured Total, n (%) 321 (8.9%) 595 (16.4%) 2710 (74.7%) 190 (8.9%) 1952 (91.1%) Age, median (range) 44 (18-64) 45 (15-64) 50 (15-64) <0.0001 75 (65-97) 76 (65-102) 0.5388 Gender, n (%) 0.0482 0.0074 Male 203 (63%) 328 (55%) 1603 (59%) 86 (45%) 1087 (56%) Female 118 (37%) 267 (45%) 1107 (41%) 105 (55%) 865 (44%) Race, n (%) <0.0001 <0.0001 White 231 (72%) 402 (68%) 2112 (78%) 131 (69%) 1724 (89%) Black 68 (21%) 114 (19%) 313 (12%) 26 (14%) 144 (7%) American Indian 2 (1%) 25 (4%) 13 (0.5%) 2 (1%) 7 (0.4%) Asian, Pacific Islander 15 (5%) 48 (8%) 215 (8%) 30 (16%) 65 (3%) Unknown 5 (2%) 6 (1%) 57 (2%) 1 (0.5%) 12 (0.6%) Hispanic Ethnicity, n (%) <0.0001 <0.0001 Non- 234 (73%) 420 (71%) 2341 (86%) 151 (79%) 1813 (93%) Hispanic Hispanic 87 (27%) 175 (29%) 369 (14%) 39 (21%) 139 (7%) Marital Status, n (%) <0.0001 <0.0001 Single 141 (46%) 281 (50%) 588 (23%) 41 (23%) 153 (9%) Married/partner 123 (40%) 194 (34%) 1652 (65%) 67 (37%) 1069 (59%) Divorced/separated/widowed 45 (15%) 90 (16%) 288 (11%) 72 (40%) 578 (32%) Figure 1. Survival of patients (A) age 15-64 and (B) age 65+ by insurance status at diagnosis. Figure 1. Survival of patients (A) age 15-64 and (B) age 65+ by insurance status at diagnosis. Disclosures Fathi: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy; Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

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Pophali, Priyanka, Melissa C. Larson, Cristine Allmer, Umar Farooq, Brian K. Link, Matthew J. Maurer, James R. Cerhan, and Carrie A. Thompson. "Compliance with Age-Appropriate Screening for Malignancies and Influenza Vaccination in 3-Year Lymphoma Survivors." Blood 132, Supplement 1 (November 29, 2018): 4791. http://dx.doi.org/10.1182/blood-2018-99-117822.

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Abstract Background: The frequency of preventive health practices (PHP), including age-appropriate screening for malignancies and immunizations, and compliance with PHP guidelines in lymphoma survivors is not known. We hypothesized that lymphoma survivors are more compliant with PHP than the general population but PHP rates may differ based on patient, disease and treatment characteristics. Methods: We identified eligible lymphoma patients from the SPORE Molecular Epidemiology Resource (MER) cohort, in which they were prospectively enrolled within <9 months of diagnosis. Survivors self-reported their PHP (colon, breast, and prostate cancer screening and influenza immunization) in the 3-year follow-up questionnaire (FU3). Per US Preventative Task Force guidelines, survivors were considered eligible for colon cancer screening if they were >50 years and compliant if they had fecal occult blood test <1 year or sigmoidoscopy/colonoscopy <10 years of FU3. Eligible female survivors age 50-75 were considered compliant if they had a mammogram after lymphoma diagnosis. Since USPTF recommended against PSA for prostate cancer screening in 2012, males aged 55-69 prior to 2012 were eligible and considered compliant if PSA test was <1 years of FU3. Survivors who received influenza vaccine <1 year of FU3 were considered compliant. Chi-square test was used to compare characteristics of compliant vs non-compliant patients; p value <0.05 was considered statistically significant. Results: Of 4248 lymphoma patients enrolled in the MER from 2002 to 2012, 2038 participants completed FU3. 1105 (54%) were male. The median age at diagnosis was 61 (IQR 51-69) years. There were equal numbers of indolent (N=1002) and aggressive (N=995) histologies with follicular (N=515, 25%) and diffuse large B-cell (N=427, 21%) being the most common. Majority (N=1221, 60%) had advanced stage (Ann Arbor III-IV) disease. 469 (23%) had events prior to FU3 and majority 1777 (88%) had received lymphoma treatment prior to FU3. Of 2038 survivors who completed FU3, 1576 (79%) reported having colon cancer screening in their lifetime. 1328 (91%) of 1570 eligible survivors were compliant, 124 (9%) were not and 118 had missing information. Survivors of age >60 years (93% vs 88%, p<0.001), those with indolent lymphomas (93% vs 90%, p=0.046), or diagnosed between 2010-2012 (94% vs 90% 2002-2009, p=0.007) were more likely to be compliant. There was no difference in colon cancer screening by sex, events prior to FU3 or treatment prior to FU3. 872 (96%) of 933 female survivors reported having a breast exam and 836 (91%) had a mammogram at least once in their lifetime. 495 (96%) of 561 eligible female survivors were compliant, 23 (4%) were not and 43 had missing information. There was no difference in mammographic screening based on age (<=60 vs >60), histology (indolent vs aggressive), events prior to FU3, treatment prior to FU3 or year of diagnosis (2010-2012 vs 2002-2009). 737 (78%) of 1105 male survivors had a PSA test at least once in their lifetime. 115 (71%) of 216 eligible men were compliant, 47 (29%) were not and 54 had missing information. There was no difference in PSA screening by age (<=60 vs >60), histology (indolent vs aggressive), events prior to FU3, and treatment prior to FU3. 1818/2038 (90%) survivors had received an influenza vaccine in their lifetime. 1567 (81%) were compliant, 373 (19%) were not and 98 had missing information. Survivors >60 years of age (87% vs 75%, p<0.001) and those with indolent lymphoma (83% vs 78%, p=0.015) were more likely to be compliant. There was no difference in influenza vaccination by sex, events prior to FU3, treatment prior to FU3, and year of diagnosis (2010-2012 vs 2002-2009). As a comparison in the US general population [Figure], between 2002-2015 the highest rates published by the Center for Disease Control are 62% for colon cancer screening (2015), 75% for mammography (insured, 2003) and influenza vaccination 42% (2015). Per the American Cancer Society, the highest rate of PSA screening was 54% (2010). Conclusion: Lymphoma survivors have high compliance with PHP recommendations compared to the general population. Although older individuals and those with indolent histologies were more likely to receive influenza vaccination and colon cancer screening, this difference was not seen in breast and prostate cancer screening practices. Lymphoma treatment and events did not seem to affect the frequency of PHP among survivors. Figure. Figure. Disclosures Cerhan: Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

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Alhaj Moustafa, Muhamad, Ricardo Parrondo, Gregory Wiseman, Jennifer Peterson, Thomas E. Witzig, and Han W. Tun. "Long-Term Outcome of Patients with Low-Grade Follicular Lymphoma Treated with Yttrium-90 Ibritumomab Tiuxetan: The Mayo Clinic Experience." Blood 134, Supplement_1 (November 13, 2019): 2809. http://dx.doi.org/10.1182/blood-2019-129391.

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Background Follicular lymphoma (FL) is the second most common lymphoma accounting for approximately 15% of all non-Hodgkin's lymphoma (NHL). Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. This study analyzed patients with previously untreated (UFL) or relapsed/refractory low-grade FL (RFL) treated at our institution with (90)Y-IT. It represents the largest reported cohort for therapeutic use of (90)Y-IT in low-grade FL. Methods Medical records of patients with low-grade FL (WHO grade 1-2) who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2003 and December 2018 were analyzed. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Our cohort consists of 137 patients - 29% (40/137) with UFL and 71% (97/137) with RFL. The median age at diagnosis was 60 years (range, 18-86) with 54% (74/137) males. The median number of previous treatments in RFL patients was 1 (range, 1-5). ECOG performance status at the time of treatment was 0 in 90% and 1 in 10% of patients. 87% (119/137) had stage III/IV disease at the time of (90)Y-IT therapy. The median follow up from the time of (90)Y-IT therapy was 10.2 years (95% CI; 8.8, 11.6); 69% (95/137) of patients are alive. The ORR was 100% in UFL with 93% (37/40) CR while ORR in UFL was 93% (90/97) with 73% (71/97) CR. 45% (48/108) of the CR patients remain in continuous CR (CCR) with a median follow-up of 7 years (95% CI; 5.2, 9.9). CCR was observed in 55% (22/40) of UFL patients compared to 27% (26/97) of RFL patients. 63% (86/137) of patients had relapsed. More relapses occurred in the RFL group (69/97; 71%) compared to the UFL group (17/40; 43%), (p=0.002). In the entire cohort, the median PFS was 2.5 years (95% CI; 2.1, 3.5) and TTNT was 3.6 years (95% CI; 2.5, 4.7). Median PFS was significantly higher in UFL group compared to RFL group- 4.1 years (95% CI; 2.3, NR) vs 2.2 years (95% CI; 1.6, 3.1), respectively (Figure 1-A). Median TTNT was higher in UFL group compared to RFL group- NR (95% CI; 4.1 years, NR) vs 2.4 years (95% CI; 2, 3.6), respectively (Figure 1-B). Median OS (entire cohort) was 18 years (95% CI; 15.8, NR) with no statistically significant difference between UFL group and RFL group; NR (95% CI; NR, NR) vs 18 years (95% CI; 12.3, 20.5), respectively (Figure 1-C). Transformation to high grade lymphoma was seen in 19% (18/97) in RFL group compared to 2.5% (1/40) in UFL group, (p=0.005). Median time to transformation was 4.3 years (range, 1-11). More patients developed therapy-related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in the RFL group 14% (14/97) compared to 2.5% (1/40) in the UFL group (p= 0.02). Median time to develop MDS/AML was 3.3 years (range, 0-9.7). Grade ³3 neutropenia was observed in 46% of patients with median time to recovery of 21 days (range, 2-706). Grade ³3 thrombocytopenia was observed in 47% of patients with median time to recovery of 23 days (range, 7-548). Eighteen patients required growth factors support and 14 required transfusions. Non-hematologic AEs included mild to severe fatigue in 35 patients. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is an effective single-agent regimen for low-grade FL. The response and survival data in this large real-world cohort is superior to the pivotal trials of this agent conducted nearly 20 years ago. The data in untreated FL is also of interest and provides the rationale for our current randomized phase 2 trial in untreated FL (https://clinicaltrials.gov/show/NCT02320292). Long-term complete remission (>7 years) was seen in 35% of the study population. Based on these promising results, clinical trials combining RIC with novel agents that could potentiate its effects are warranted. Figure 1 (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UFL) and patients with relapsed/refractory FL (RFL), (B) Time to next therapy; comparing time to starting next line of treatment after (90)Y-IT treatment between UFL and RFL, (C) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UFL and RFL. Figure 1 Disclosures Tun: DTRM Biopharma: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; Curis: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. We are discussing its use as a frontline therapy in low grade FL.

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Silva, Janaina Soares, Rejane Kelly Andrade Beiriz, Marcus Antônio Brêda Júnior, Ricardo Viana Bessa-Nogueira, Marcelo Marotta Araujo, and Ricardo José Holanda Vasconcellos. "Fixação interna estável de fratura condilar: relato de caso." ARCHIVES OF HEALTH INVESTIGATION 9, no. 6 (September 23, 2020): 541–45. http://dx.doi.org/10.21270/archi.v9i6.5127.

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As fraturas mandibulares são o segundo tipo de fraturas mais comum que acomete a face, e elas podem ter um impacto negativo na estética e anatomia facial, bem como causar problema em atividades cotidianas como falar e mastigar. Este artigo tem por objetivo relatar o caso clínico de um paciente vítima de agressão física, que apresentou uma fratura unilateral de côndilo associada à fratura oblíqua de sínfise. Paciente do gênero masculino, 32 anos, leucoderma, através das radiografias PA de mandíbula e Towne foram constatadas fratura da região de sínfise mandibular e côndilo do lado esquerdo. A escolha para o tratamento desta fratura, foi o tratamento cirúrgico com fixação interna da fratura condilar com sistema 2.0mm. Após sete dias foi iniciada a fisioterapia com espátulas de madeira para o restabelecimento de adequada abertura bucal, apresentando ao final uma recuperação satisfatória, sem intercorrências. O uso de placas e parafusos para o tratamento cirúrgico de fraturas de côndilo mandibular e sínfise se mostrou eficaz, resultando no sucesso cirúrgico com um pós-operatório sem complicações e no reestabelecimento funcional e da oclusão. Descritores: Fraturas Mandibulares; Côndilo Mandibular; Fixação de Fratura. Referências Bastos EO, Goldenberg DC, Alonso N. Acesso retromandibular transparotídeo: uma via simples, eficaz e segura para tratamento das fraturas de côndilo mandibular. Rev Soc Bras Cir Craniomaxilofac. 2009;12(1):10-5. Araújo CFSN, Braga PLS, Ferreira JDB. Tratamento tardio de fratura condilar: Relato de caso. Rev cir traumatol buco-maxilo-fac. 2013;13(3):17-24. Gois Filho DM, Amarante AS, Moura RQ, Dultra JA, Carneiro Júnior B. Uso do acesso retromandibular para tratamento de fratura bilateral de côndilo mandibular: relato de caso. Rev cir traumatol buco-maxilo-fac. 2013;13(1):29-34. Rodrigues CMC, Santos DM, Oliveira MMM, Silva MCP, Furtado LM. Tratamento conservador de fratura condilar alta: relato de caso. Rev Odontol Bras Central. 2019;28(85):87-90. Mendonça JCG, Bento LA, Freitas GP. Tratamento das fraturas de côndilo mandibular: revisão da literatura. Rev Bras Cir Craniomaxilofac. 2010;13(2):102-6. Ellis E 3rd, Throckmorton G. Facial symmetry after closed and open treatment of fractures of the mandibular condylar process. J Oral Maxillofac Surg. 2000;58(7):719-28;729-30. Dantas BPSS, Fialho PV, Fernandes ACF, Silva DT, Queiroz CS. Fratura complexa de mandíbula: relato de caso. Rev Odontol Araçatuba. 2017;38(3):43-8. Trento G, Corso PFCL, Scariot R, Kluppel LE, Costa DJ, Rebellato NLB. Tratamento cirúrgico de fratura da cabeça de mandíbula com parafusos bicorticais: relato de caso. Arq bras odontol. 2014;10(2):12-9. Bagheri SC, Bell RB, Khan HA. Terapias atuais em cirurgia bucomaxilofacial. Rio de Janeiro: Elsevier; 2013. Manganello LC, Silva Alexandre AF. Fraturas do Côndilo Mandibular: classificação e tratamento. Rev Bras Otorrinolaringol. 2002;68(5):249-55. Vieira WM, Siqueira OV, Scherma AP, Miranda LR. Fratura bilateral de côndilo mandibular: tratamento tardio e complicações. Rev Bras Cir Craniomaxilofac. 2011;14(2):115-18. Rampaso CL, Mattioli TMF, Andrade Sobrinho J, Rapoport A. Avaliação da prevalência do tratamento das fraturas de côndilo mandibular. Rev Col Bras Cir. 2012;39(5):373-76. Pogrel MA, Kahnberg KE, Andersson MA. Cirugia Bucomaxilofacial. Rio de Janeiro: Santos; 2016. Alencar MGM, Rebelo HL, Silva EZ, Breda Junior MA, Medeiros Junior MD. Tratamento de fratura complexa de mandíbula por abordagem transcervical: Relato de caso. Rev cir traumatol buco-maxilo-fac. 2015; 15(4):43-8. Rampaso CL, Mattioli TMF, Sobrinho JA. Rapoport Estudo epidemiológico das fraturas do côndilo da mandíbula. Rev Bras Cir Cabeça Pescoço. 2009;38(1):19-21. Ramalho RA, Farias Junior ON, Cardoso AB. Tratamento cirúrgico de fratura bilateral de côndilo associada à fratura de corpo mandibular: relato de caso. Rev cir traumatol buco-maxilo-fac. 2013;13(2):69-73. Kumaran S, Thambiah LJ. Analysis of two different surgical approaches for fractures of the mandibular condyle. Indian J Dent Res. 2012;23(4):46-68. Valiati R, Ibrahim D, Abreu ME, Heitz C, de Oliveira RB, Pagnoncelli RM, Silva DN. The treatment of condylar fractures: to open or not to open? A critical review of this controversy. Int J Med Sci. 2008;5(6):313-18. Choi KY, Yang JD, Chung HY, Cho BC. Current concepts in the mandibular condyle fracture management part I: overview of condylar fracture. Arch Plast Surg. 2012;39(4):291-300. Ellis E, Throckmorton GS. Treatment of mandibular condylar process fractures: biological considerations. J Oral Maxillofac Surg. 2005;63(1):115-34. Iwaki Filho L, Pavan AJ, Camarini ET, Tondin GM. Tratamento das fraturas de côndilo mandibular: cirúrgico ou conservador? Rev cir traumatol buco-maxilo-fac. 2005;5(4):17-22.

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Imataki, Osamu, Shumpei Uchida, Maki Oku, Shigeyuki Yokokura, Makiko Uemura, and Norimitsu Kadowaki. "the Charlson Comorbidity Index Predicts Survival Following Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia Patients." Blood 126, no. 23 (December 3, 2015): 5146. http://dx.doi.org/10.1182/blood.v126.23.5146.5146.

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Abstract Background: Comorbidity may influence the treatment and long-term quality of life of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The Charlson Comorbidity Index (CCI) assesses comorbidity by taking into account the severity of 19 precedent comorbid conditions [J Chron Dis 1987; 40: 373]. The CCI was originally introduced as a measure of the mortality risk of general hospitalized patients, and it can estimate the risk of morbidity in a patient with any medical background. The CCI has been validated to predict patients' life expectancy in various underlying diseases, and it is widely used for both hospitalized patients and outpatients. We evaluated the risk of comorbidity at the diagnosis of CML to determine whether treatment with tyrosine kinase inhibitors (TKIs) results in longer survival in a cohort of Japanese patients. Patients and method: We used a chart review to survey CML patients diagnosed between November 2001 and December 2012 in Kagawa, Japan, where we collected all of the patients based on their registration in another population-based study. Inclusion criteria were (1) diagnosis of CML in the chronic phase during the study period and (2) treatment by TKIs at any point of the study period. Patients of all ages were included. The available TKIs were imatinib, nilotinib and dasatinib. We did not exclude patients treated with two or more TKIs. We used the CCI to evaluate concomitant underlying disease at diagnosis, and we calculated the Sokal and Hasford scores to compare the predictability of prognosis with the CCI at diagnosis. We used the Sokal and Hasford scores as the standard reference. Results: Eighty (47 male, 33 female) cases were enrolled (median age 56 yrs, range 6-89 yrs). The distribution of CCI scores at diagnosis were 2-11 (median 2). The initial treatment was started in 73 cases by imatinib, two cases by nilotinib, and four by dasatinib (one is unknown). Only one patient underwent stem cell transplantation after 2-yr treatment by imatinib, because of the development of myelodysplastic syndrome (this case was not censored.) As of the last follow-up, the treatment responses were 46 major molecular responses (MMRs), 12 complete cytogenetic responses (CCyRs) and 14 complete hematological responses (CHRs). Seventy-five percent of the cases (60/80) achieved CCyR at 12 mos after TKI administration. We observed only five deaths during the 55.5-mos median follow-up period (0.3-217 mos; 3 pneumonia, 1 cancer and 1 unknown cause). The number of patients according to the given CCI comorbidity risk categories are presented in Table 1. The patient numbers in the risk categories (low/intermediate/high) per the Sokal and Hasford scores were 33/27/7 and 21/43/3, respectively. The CCI scores were significantly correlated with the Sokal and Hasford scores (R >0.5). Twenty-seven cases with a CCI score ≥3 (52 cases had CCI <2) had significantly poor survival both from diagnosis (log rank, P=0.0136) and from TKI treatment (P =0.0025). The most common CCI comorbidity factor was 'diabetes without organ failure.' The most serious comorbidity was 'metastatic cancer,' seen in four cases. CCI scores were inversely associated with overall survival (R = −0.11). Discussion: In CML, concomitant comorbidity at diagnosis is more strongly associated with survival, especially after TKI treatment compared to after diagnosis. This suggests that TKI treatment may influence patients' health conditions by contributing to the induction of adverse events. Thus, the clinical impact of CCI for CML patients treated with TKIs is supplemental, but CCI is useful to take care of the patient. Table 1. Numbers of patients according to the given comorbidity risk categories of CCI A. Myocardial Infarction (1 point) 1 B. Congestive Heart Failure (1 point) 3 C. Peripheral Vascular Disease (1 point) 1 D. Cerebrovascular Disease (1 point) 1 E. Dementia (1 point) 5 F. COPD (1 point) 4 G. Connective Tissue Disease (1 point) 1 H. Peptic Ulcer Disease (1 point) 2 I. Diabetes Mellitus (1 point uncomplicated, 2 points if end-organ damage) 7 and 2 J. Moderate to Severe Chronic Kidney Disease (2 points) 2 K. Hemiplegia (2 points) 1 L. Leukemia (2 points) 80 M. Malignant Lymphoma (2 points) 0 N. Solid Tumor (2 points, 6 points if metastatic) 2 and 3 O. Liver Disease (1 point mild, 3 points if moderate to severe) 3 and 0 P. AIDS (6 points) 0 Disclosures No relevant conflicts of interest to declare.

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Ritchlin, C. T., P. J. Mease, W. H. Boehncke, J. Tesser, E. Schiopu, S. D. Chakravarty, A. Kollmeier, et al. "AB0526 SUSTAINED GUSELKUMAB RESPONSE IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS REGARDLESS OF BASELINE DEMOGRAPHIC AND DISEASE CHARACTERISTICS: POOLED RESULTS THROUGH WEEK 52 OF TWO PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED STUDIES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1291–92. http://dx.doi.org/10.1136/annrheumdis-2021-eular.437.

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Background:In the Phase 3 DISCOVER-11 & DISCOVER-22 trials, guselkumab (GUS), a human monoclonal antibody targeting the IL-23p19-subunit, was effective in psoriatic arthritis (PsA) across joint & skin endpoints. At Week 24 (W24), GUS benefit was consistent regardless of baseline (BL) demographic & disease characteristics.3Objectives:We assessed whether GUS efficacy was sustained through W52 in pooled DISCOVER-1 & -2 patients (pts) across select BL subgroups.Methods:Adults with active PsA despite standard therapies were enrolled in DISCOVER-1 (swollen [SJC] ≥3 & tender joint count [TJC] ≥3, C-reactive protein [CRP] ≥0.3 mg/dL) & DISCOVER-2 (SJC ≥5 & TJC ≥5, CRP ≥0.6 mg/dL). 31% of DISCOVER-1 pts had received 1-2 prior tumor necrosis factor inhibitors; DISCOVER-2 pts were biologic naïve. Pts were randomized 1:1:1 to GUS 100 mg every 4 weeks (Q4W); GUS 100 mg at W0, W4, then Q8W; or placebo (PBO). Pts randomized to PBO received GUS 100 mg Q4W starting at W24 & were excluded from these analyses assessing maintenance of effect from W24 to W52. GUS effects on joint (American College of Rheumatology [ACR]20/50/70) & skin (Investigator’s Global Assessment [IGA=0/1 + ≥2-grade reduction from W0] in pts with ≥3% body surface area [BSA] with psoriasis & IGA ≥2 at W0) endpoints were evaluated by pt BL SJC, TJC, conventional synthetic disease-modifying antirheumatic drug (csDMARD) use, body mass index (BMI), PsA duration, & % BSA with psoriasis. Missing data were imputed as nonresponse through W52.Results:BL pt characteristics in DISCOVER-1 (N=381) & DISCOVER-2 (N=739) were well balanced across randomized groups.1,2 Among 1120 pooled pts, mean SJC was 11, mean TJC was 21, & 68% used csDMARDs (primarily methotrexate [MTX]). At W24, 62% (232/373) & 60% (225/375), respectively, of GUS Q4W- & Q8W-treated pts achieved ACR20 vs 29% (109/372) of PBO, with GUS effect consistently observed across pt BL subgroups (Figure 1). ACR20 response rates were sustained or increased at W52 in the GUS Q4W (72%) & Q8W (70%) groups & across SJC (61-79%), TJC (68-76%), & csDMARD use (68-80%) subgroups (Table 1) & pt subgroups defined by BL BMI, PsA duration, & % BSA with psoriasis (data not shown). ACR50 & 70 response patterns were similar to ACR20 (Table 1). In pts with ≥3% BSA psoriasis & IGA ≥2 at BL, 71% (193/273) & 66% (171/258) of GUS Q4W- & Q8W-treated pts, respectively, vs 18% (47/261) of PBO, achieved IGA 0/1 at W24, with GUS effect consistently observed across pt BL subgroups (Figure 1). IGA 0/1 response rates were also sustained or increased at W52 in the GUS Q4W (80%) & Q8W (71%) groups & across % BSA with psoriasis (67-87%) & csDMARD use (68-87%) subgroups (Table 1) & pt subgroups defined by BL BMI and PsA duration (data not shown).Conclusion:Treatment with GUS 100 mg Q4W & Q8W resulted in sustained improvement in signs & symptoms of active PsA through W52 regardless of pt BL characteristics.References:[1]Deodhar A, et al. Lancet 2020;395:1115-25;[2]Mease P, et al. Lancet 2020;395:1126-36;[3]Deodhar A, et al. American College of Rheumatology 2020; Poster P0908.Figure 1Figure 1Table 1.ACR & IGA Responses at Weeks 24 & 52 & by Select BL CharacteristicsGuselkumab Q4WGuselkumab Q8WN=373N=375Week 24Week 52Week 24Week 52ACR20, %62726070 SJC (<10/10-15/>15)68/59/5379/61/6757/66/6068/68/76 TJC (<10/10-15/>15)74/67/5673/76/6962/60/6075/68/68 csDMARD use (none/any/MTX)66/60/6380/68/6862/59/5773/68/68ACR50, %34493145 SJC (<10/10-15/>15)41/32/2058/39/3834/28/2646/40/49 TJC (<10/10-15/>15)51/41/2458/53/4340/33/2652/46/43 csDMARD use (none/any/MTX)36/33/3553/46/4836/29/2751/42/40ACR70, %16271627 SJC (<10/10-15/>15)22/10/732/20/2418/10/1930/23/26 TJC (<10/10-15/>15)29/19/934/32/2227/15/1435/28/24 csDMARD use (none/any/MTX)21/13/1430/26/2721/14/1434/24/23N=273N=258IGA 0/1, %71806671 BSA % with psoriasis(≥3-<10/≥10-<20/≥20)61/71/8076/87/7962/64/7267/72/74 csDMARD use (none/any/MTX)84/64/6787/77/7872/63/6477/68/68Disclosure of Interests:Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, and UCB Pharma, Grant/research support from: AbbVie, Amgen, and UCB Pharma, Philip J Mease Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Novartis, Pfizer, SUN, and UCB Pharma, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, SUN, and UCB Pharma, Wolf-Henning Boehncke Speakers bureau: AbbVie, Almirall, Celgene, Janssen, Leo, Eli Lilly, Novartis, UCB Pharma, Consultant of: AbbVie, Almirall, Celgene, Janssen, Leo, Eli Lilly, Novartis, UCB Pharma, Grant/research support from: Pfizer, John Tesser Speakers bureau: AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Crescendo Biosciences/Myriad, GlaxoSmithKline, Genentech, Janssen, Eli Lilly, and Pfizer, Consultant of: AbbVie, AstraZeneca, Bristol Myers Squibb, Gilead, Janssen, Eli Lilly, Novartis, and Pfizer, Grant/research support from: AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Horizon, Janssen, Eli Lilly, Merck KG, Novartis, Pfizer, Sandoz, Sun Pharma, Setpoint, and UCB Pharma, Elena Schiopu Consultant of: Janssen, Grant/research support from: Janssen, Soumya D Chakravarty Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Scientific Affairs, LLC, Alexa Kollmeier Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Elizabeth C Hsia Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Xie L Xu Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, May Shawi Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Global Services, LLC, Yusang Jiang Employee of: Cytel, Inc., providing statistical support (funded by Janssen), Shihong Sheng Shareholder of: Johnson & Johnson, of which Janssen Research & Development is a wholly owned subsidiary, Employee of: Janssen Research & Development, LLC, Joseph F. Merola Consultant of: AbbVie, Arena, Biogen, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sun Pharma, and UCB Pharma, Iain McInnes Consultant of: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, and UCB Pharma, Grant/research support from: Bristol Myers Squibb, Celgene, Eli Lilly, Janssen, and UCB Pharma, Atul Deodhar Speakers bureau: AbbVie, Amgen, Eli Lilly, Janssen, Novartis, Pfizer, UCB Pharma, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer, UCB Pharma, Grant/research support from: AbbVie, Eli Lilly, GlaxoSmithKline, Novartis, Pfizer, UCB Pharma.

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Kimura, Kenji, Shokichi Tsukamoto, Kanji Miyazaki, Chika Kawajiri-Manako, Bahityar Rahmutulla, Masaki Fukuyo, Nagisa Oshima-Hasegawa, et al. "Identification of Clonal Immunoglobulin λ Light-Chain Gene Rearrangements in AL Amyloidosis Using Next Generation Sequencing." Blood 134, Supplement_1 (November 13, 2019): 1748. http://dx.doi.org/10.1182/blood-2019-125028.

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[Introduction] AL amyloidosis is caused by the deposition of abnormally folded clonal immunoglobulin (IG) light chains (LCs, λ:κ = 3:1) made by malignant plasma cells in the bone marrow (BM), which leads to multi-organ dysfunction, often involving the heart, kidney, liver, skin, and nerves. However, little is known about what regulates organ tropism of amyloid deposition in this disease. In addition, no study has analyzed the repertoire of IG germlines of plasma cells in the BM in AL amyloidosis using next generation sequencing (NGS). In this study, we aimed to identify the clonal composition of IG λ light-chain variable region (IGLV) genes in BM cells in patients with AL amyloidosis using NGS. [Material and method] BM cells were obtained at diagnosis from 38 patients with AL amyloidosis and those with other plasma cell disorders: multiple myeloma (MM, n = 7), and monoclonal gammopathy of undetermined significance (MGUS, n = 11) with λ-type monoclonal paraprotein. Seven normal control (NC) patients had either immune thrombocytopenia or malignant lymphoma without BM invasion. Genomic DNA was extracted from the BM mononuclear cells preserved in LABO Banker1 or BM clots in O.C.T compound using QIAamp DNA Blood Mini kit. The IGLV1 and IGLV2 genes were amplified by polymerase chain reaction using a 5′ primer for the IGLV1/2 framework 3 (FR3) region and 3′ consensus primers for the IGLJ1/2/3 joining regions. Multiple samples were pooled, and paired-end 2 × 250 base pair sequencing reactions were performed using an Illumina MiSeq sequencer and then analyzed by an open-source program called Vidjil. All subjects provided written informed consent to participate in the study, in accordance with the Declaration of Helsinki. This study was approved by the ethics committee of the Chiba University Graduate School of Medicine and Japanese Red Cross Medical Center. [Results] Clinical and laboratory features of 38 patients with AL amyloidosis were as follows: primary AL amyloidosis (n = 31); 15 and 20 patients had cardiac and renal dysfunctions, respectively, and secondary AL amyloidosis with MM (n = 7); 4 and 1 patient had cardiac and renal dysfunctions, respectively. In patients with AL amyloidosis, the median plasma cell count in BM aspirate smears was 3.3% (0.1%-50.4%), and the median difference in involved and uninvolved light chains (dFLC) was 104.5 mg/L (28.5mg/L -2673.3mg/L). Representative results of the Vidjil analysis in NC, MGUS, AL amyloidosis, and MM are shown in Figure 1. The most abundant IGLV gene accounted for not >1% of the reads, and there was no dominant germline in NC samples. Therefore, we defined the dominant clone as >1% of IG germlines in plasma cells. According to this definition, clonal IG germlines were found in 27 of 31 patients with primary AL amyloidosis (87%), 5 of 7 with secondary AL amyloidosis (71%), 7 of 7 with MM (100%), and 8 of 11 with MGUS (73%). However, the size of clones in AL amyloidosis (median 3.1%, 0.38%-14.3%) was significantly smaller than that in MM (median 17.8%, 2.2%-17.9%) (P<0.001), and similar to that in MGUS (median 3.8%, 0.4%-32.0%). Importantly, in patients with AL amyloidosis, the dFLC and involved/uninvolved FLC ratio was not correlated with the clonal size of plasma cells in our repertoire analysis using NGS, suggesting that small malignant clones of plasma cells may secret FLC and cause LC depositions in AL amyloidosis. Regarding IGLV germline usage, IGLV1-51 was the most frequent repertoire in AL amyloidosis with heart dysfunction (7 of 16 cases) and renal dysfunction (7 of 21 cases). No relationship between the IGLV germlines and organ tropisms was observed. [Conclusion] We successfully identified the clonal composition of IGLV genes in the BM of most patients with AL amyloidosis using NGS, according to the differences in the V and J region recombination and CDR3 sequences using the Vidjil program. In AL amyloidosis, the clonal size of plasma cells in the BM is small and small malignant clones of plasma cells may secret FLC and cause LC depositions in AL amyloidosis. Figure 1 Disclosures Suzuki: Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria.

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