Gila Sellam | Roche Products Ltd (original) (raw)

Papers by Gila Sellam

Hematological Oncology, Jun 1, 2021

Pediatric Research, Nov 1, 2010

Background and aim: A high standard of communication between staff and parents in the neonatal un... more Background and aim: A high standard of communication between staff and parents in the neonatal unit is a vital part of family centered care. It is essential to the establishment of good working relationships and improves parent-baby bonding. Information provided should be free of medical jargon and presented in a way that parents can easily understand. We aimed to study parents' perception of the quality of communication in the neonatal unit. Method: A twelve point questionnaire was sent by post to the parents of babies admitted to the neonatal unit from August-October 09. Results: A total of 134 parents were approached and 74(55%) responded. Of the responses 50 (68%) were from mothers and 22 (30%) were from both parents. Gestational age ranged from 28-43 weeks (Median 39.5 weeks) and birth weight from 592-5020 grams (Median 3165 grams).

European Journal of Pain, Jul 2, 2012

Background: Evidence indicates that medical and demographic contextual factors (cFs) impact pain ... more Background: Evidence indicates that medical and demographic contextual factors (cFs) impact pain responses in preterm neonates, but the existing evidence is very heterogeneous. Aim: To explore the effect of cFs on pain responses to heel-stick procedures of preterm infants. Methods: This study was a secondary analysis of data collected during a randomized controlled trial examining pain response to nonpharmacological interventions across repeated heel sticks. Five heel sticks across the first 14 days of life were videotaped. Pain response was rated with the Bernese Pain Scale for Neonates (BPSN) by four raters blinded to the heel-stick phases (baseline, heel stick, recovery). Demographic and medical cFs were extracted from medical charts. Mixed single and multiple regression analyses were performed controlling for the intervention group, site and heel-stick phase. Results: Apgar scores at 1 min were negatively associated with behavioural (p = 0.002) BPSN scores, while Apgar scores at 5 min after birth were positively associated with behavioural (p = 0.006) scores. Accumulated number of painful procedures (p = 0.002) and gender (p = 0.02) were positively associated with physiological scores while continuous positive airway pressure CPAP (p = 0.009) and mechanical ventilation (p = 0.005) were negatively associated. Conclusion: Higher exposure to painful procedures, male infants and having CPAP or mechanical ventilation were cFs associated with physiological response. The only variables significantly associated with behavioural BPSN scores were Apgar scores but these relationships were inconsistent.

Acta Paediatrica, May 28, 2013

AimTo compare the influence of three different nonpharmacological interventions on cortical activ... more AimTo compare the influence of three different nonpharmacological interventions on cortical activation, heart rate and peripheral oxygen saturation (SaO2) after heelstick in preterm infants.MethodsTwenty five preterm infants between 24 0/7 and 32 0/7 weeks of gestational age were randomized to either oral sucrose (S), facilitated tucking (FT) or a combination of the two interventions (SFT) prior to five heelsticks each within the first 14 days of life. SaO2, heart rate and oxygenation of the somatosensory cortex, measured by near infrared spectroscopy (NIRS), were analysed.ResultsHundred and twenty five heelsticks were performed. The heart rate increased significantly after heelstick in all three intervention groups (p < 0.004 in all groups). The increase was higher in the FT group compared with the other groups (S: p = 0.007; SFT: p = 0.004). There was no difference among the two groups receiving sucrose (S and SFT; p = 0.87). SaO2 did not change significantly after heelstick in all intervention groups. Near infrared spectroscopy measurements did not show a significant change in the curve but patients in the FT group showed a trend towards higher average oxygenation of the contralateral somatosensory cortex.ConclusionOral sucrose seems to be more effective in reducing reaction to pain than FT. Application of both interventions did not show an additive effect.

Pediatrics, Feb 1, 2012

Preterm infants are exposed to inadequately managed painful procedures during their NICU stay, wh... more Preterm infants are exposed to inadequately managed painful procedures during their NICU stay, which can lead to altered pain responses. Nonpharmacologic approaches are established for the treatment of single painful procedures, but evidence for their effectiveness across time is lacking.

Acta Paediatrica, Jul 6, 2010

There is an impressive body of knowledge on pain management in infants hospitalized in neonatal i... more There is an impressive body of knowledge on pain management in infants hospitalized in neonatal intensive care units. However, deficits in the clinical management of pain in these infants remain. One reason is the gap between research evidence and translation of this knowledge into the clinical setting. This is particularly true for non-pharmacological painrelieving methods. Effective performance of some of these methods requires additional staffing and time. This viewpoint articles describes the clinical challenges associated with implementing 'facilitated tucking'. Although 'facilitated tucking' is described as an efficient method for acute pain relief, the clinical facilitators required to successfully implement such a resource consuming-intervention remain unclear. Conclusion: Translational research on the feasibility of using 'facilitated tucking' in the management of neonatal pain is warranted, including the economic impact of this intervention. Increased manpower costs need to be weighed against the possible long-term economical consequences of pain exposure in infants.

European Journal of Pain, Aug 1, 2011

Major efforts to develop objective measurement tools for neonatal pain assessment have been made.... more Major efforts to develop objective measurement tools for neonatal pain assessment have been made. However, the challenge of measuring pain in neonates remains suggesting that contextual factors (cFs) might alter their responses to pain. Although the role of cFs is increasingly discussed as crucial for pain assessment, they are not well described in the literature and are rarely considered in the clinical setting despite their importance.Aim: To systematically examine studies investigating the impact of cFs on pain response in preterm infants.Method: A literature search was undertaken for the period from 1990 to 2009. Studies reporting the relation between one or more cFs and pain response in preterm infants during a heelstick procedure were considered for inclusion.Results: Twenty‐three studies satisfied inclusion criteria. The studies varied relative to their design, sample, analysis procedures, and variables examined. Six categories of cFs emerged: age, pain exposure, health status, therapeutic interventions, behavioral status, and demographic factors. The examined cFs varied in the strength of their association with pain response, although none were invariably related, as evidenced by contradictory findings. In some cases the inconsistencies appeared attributable to methodological limitations in studies. Behavioral and physiological pain responses were not always in agreement as would be expected.Conclusion: This review supports the influence of some cFs on pain response. However, the results remain inconclusive which may be, in part, related to the heterogeneity of the studies. Contextual factors need further investigation for a better understanding of the magnitude of their effect on pain response.

Blood, Nov 13, 2019

Introduction: Multiple response criteria have been proposed for the assessment of treatment respo... more Introduction: Multiple response criteria have been proposed for the assessment of treatment response in lymphoma patients (pts). The Lugano 2014 criteria have been adopted as the current standard for response assessment in lymphoma (Cheson et al. J Clin Oncol 2014), incorporating 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas. For non-FDG avid lymphomas, and when PET is not available, Lugano criteria use bi-dimensional tumor measurements of up to six CT target lesions. The more recently proposed Response Evaluation Criteria in Lymphoma (RECIL) (Younes et al. Annals Oncol 2017) were developed based on the hypothesis that uni-dimensional measurements of up to three target lesions could be used to assess response at a similar level of accuracy to the Lugano criteria. The prognostic value of Lugano 2014 versus RECIL 2017 criteria has not yet been assessed in large clinical trials. We compared the prognostic performance of Lugano and RECIL criteria in pts from the Phase III GOYA study (NCT01287741), which compared the efficacy of obinutuzumab (GA101, G) and rituximab (R) in combination with CHOP (G-CHOP vs R-CHOP) in previously untreated pts with CD20-positive DLBCL. Methods: In the GOYA study, pts were randomized 1:1 to receive either G-CHOP or R-CHOP (stratification factors: number of planned chemotherapy cycles, International Prognostic Index [IPI], and geographic region). FDG-PET scans were mandatory at sites where a PET scanner was available and were performed at screening and 6-8 weeks after the last study treatment. Response was assessed prospectively based on Cheson 2007 criteria and retrospectively according to standard Lugano 2014 criteria. A retrospective analysis based on RECIL 2017 criteria was also performed. Response categories by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. The impact of covariates on PFS and OS were analyzed using a multivariate Cox model. Landmark analyses of PFS and OS according to end of treatment (EoT) complete response (CR)/non-CR status were performed, and the prognostic value of response at EoT was compared for the two methods. Results: Of the 1418 pts (intention-to-treat [ITT] population) in the GOYA study, 1334 had PET data and were evaluable for this analysis. Good agreement between Lugano and RECIL criteria was observed for EoT CR status, with 894/966 (92.5%) pts with a complete metabolic response (CMR) by Lugano classified as CR by RECIL (Table). However, 40/63 (63.5%) pts with progressive metabolic disease (PMD) at EoT according to Lugano criteria had a partial response (PR) or minor response (MR) by RECIL criteria, showing poor agreement for these variables. Of the 43 pts with PMD by Lugano and non-PD by RECIL at EoT, 15 pts had no PFS event by Lugano as assessed by CT and could be considered false positives. Concordance for PFS by CT was high between the two criteria, with a kappa estimate of 0.77 (95% CI: 0.74, 0.80). EoT CR status by RECIL was highly prognostic for PFS (stratified HR, 0.32; 95% CI: 0.25, 0.43; p<0.0001) and OS (stratified HR, 0.26; 95% CI: 0.19, 0.36; p<0.0001), with a similar prognostic performance as the Lugano criteria (PFS HR, 0.31; 95% CI: 0.23, 0.41; p<0.0001). Multivariate analysis confirmed that EoT CR status by RECIL was prognostic for both PFS (HR, 0.18; 95% CI: 0.15, 0.23; p<0.0001) and OS (HR, 0.23; 95% CI: 0.17, 0.32; p<0.0001), independent of the stratification factors (IPI, number of planned CHOP cycles, geographic region). Assessment with RECIL criteria provided similar PFS results to GOYA for the comparison of G- vs R-CHOP (RECIL: HR, 0.95; 95% CI: 0.78, 1.17; p=0.64; GOYA: HR, 0.94; 95% CI: 0.78, 1.12; p=0.47). Conclusions: EoT CR status according to RECIL 2017 criteria showed a high concordance with CMR status by Lugano 2014 criteria and was highly prognostic for PFS and OS in previously untreated DLBCL; however, discordance was seen for the identification of PD by RECIL compared with Lugano criteria. PFS as assessed by CT by RECIL, based on uni-dimensional size measurements of up to three target lesions, showed high concordance with PFS by Lugano criteria, based on bi-dimensional size measurements of up to six target lesions. Table Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck:…

Blood, Dec 7, 2017

Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomog... more Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, <25%; Q2, 25-50%; Q3, 50-75%; and Q4, 75-100%, which were obtained based on their distribution in the available population. The reported hazard ratios (HRs) refer to stratified log-rank tests comparing Q2, Q3, and Q4 to Q1, adjusted for stratification factors of the study: IPI score (low [0-2], intermediate [3], and high [4-5]) and number of planned CHOP cycles (6 or 8). Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p<0.0001, and HR=1.91, 95% CI 1.28-2.85, p=0.0005, respectively. TMTV was also predictive of overall survival (OS): HR=2.63, 95% CI 1.55-4.46; p<0.0001. However, SUVmax-based prediction of PFS was not statistically significant (HR=0.84, 95% CI 0.57-1.23, p=0.3782). Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche:…

Blood, Dec 7, 2017

Introduction: Reactivation of hepatitis B virus (HBV) is an identified risk associated with immun... more Introduction: Reactivation of hepatitis B virus (HBV) is an identified risk associated with immunochemotherapy for non-Hodgkin lymphoma (NHL) in patients (pts) with resolved HBV infection. This study aimed to evaluate the risk of HBV reactivation and explore risk factors in NHL pts with resolved HBV infection who received anti-CD20 antibody (obinutuzumab or rituximab)-containing immunochemotherapy in the phase III GOYA and GALLIUM studies (involving pts with previously untreated diffuse large B-cell lymphoma [DLBCL] and indolent NHL, respectively). Methods: Pts were randomized to receive induction with either obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2‒8) or rituximab (375 mg/m2 on day 1 of each cycle) in combination with CHOP (GOYA and GALLIUM), CVP (GALLIUM), or bendamustine (GALLIUM) for 6-8 cycles. In GALLIUM, induction was followed by obinutuzumab or rituximab maintenance. Baseline screening was performed locally for hepatitis B surface antigen (HBsAg) and antibody against hepatitis B core antigen (anti-HBc). Pts positive for HBsAg were excluded, while those with resolved HBV infection (HBsAg-negative but anti-HBc-positive) could be enrolled if they had baseline HBV DNA Results: Of 2797 evaluable pts (GOYA, 1407; GALLIUM, 1390), 326 pts were seropositive for anti-HBc (207 were seropositive for antibodies against HBsAg) and 11 had detectable but non-quantifiable HBV DNA (10 to Conclusions: HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during treatment with obinutuzumab- or rituximab-containing immunochemotherapy. Antiviral prophylaxis was effective in preventing HBV reactivation and may be an appropriate option for pts with resolved HBV infection and multiple risk factors. Disclosures Kusumoto: Chugai: Honoraria, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of Shigeru Kusumoto, was provided by Cheryl Wright of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Arcaini: Celgene, Roche, Sandoz: Consultancy; Gilead: Research Funding; Pfizer, Celgene, Bayer, Roche: Membership on an entity9s Board of Directors or advisory committees. Kim: JJ Takeda: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Kyowa-Kirin: Research Funding. Peters: Genentech, Merck: Honoraria; Roche: Honoraria. Tanaka: BMS: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; GSK: Honoraria, Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Kuriki: Chugai: Employment. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ueda: Chugai: Employment. Piper-Lepoutre: Roche: Employment. Sellam: Roche: Employment. Tobinai: Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; AbbVie: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria.

Blood, Nov 29, 2018

Introduction: Clinical trial response assessments for follicular lymphoma (FL) and diffuse large ... more Introduction: Clinical trial response assessments for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) typically mandate bone marrow biopsies (BMBs) at baseline and for confirmation of complete response (CR) as assessed by computed tomography (CT) imaging according to International Working Group (IWG) criteria. BMBs are painful and expensive, and can deter patients (pts) from clinical trial participation. Rutherford et al. (Br J Haematol 2017) suggested that confirmatory BMBs do not impact response assessment in the majority of FL pts treated in clinical trials. We describe the impact of confirmatory BMBs on response in the GALLIUM study (NCT01332968), which randomized previously untreated FL pts to obinutuzumab (G)- or rituximab (R)-chemotherapy (CHOP, CVP, or bendamustine) followed by maintenance with the same antibody in responders, and in the GOYA study (NCT01287741), which randomized previously untreated DLBCL pts to G-CHOP or R-CHOP. Methods: We conducted a retrospective analysis of GALLIUM and GOYA to evaluate the percentage of pts with CR as assessed by CT but with a positive BMB at end of induction (EOI), and the percentage of pts with complete metabolic response (CMR) on positron emission tomography (PET) by Lugano 2014 criteria but with a positive BMB at EOI. Response by PET was an exploratory endpoint and not mandatory. Results: Of 1202 randomized FL pts in GALLIUM, 633 (52.7%) had a positive (613 pts, 51.0%) or indeterminate (20 pts, 1.7%) baseline BMB (data missing for 12 pts, 1.0%). Bone marrow involvement was not prognostic for progression-free survival (PFS; investigator (INV)-assessed PFS: HR 0.99 [95% CI 0.80, 1.23] for pts with positive vs non-positive BMB). At EOI, 209/633 (33%) pts had a CR on CT by IWG criteria, 179 of whom had a follow-up BMB to confirm response; 174/179 (97.2%) had a negative BMB that confirmed CR, 1/179 (0.6%) was positive, and 4/179 (2.2%) were indeterminate. Overall, only 5/179 (2.8%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 5/1202 (0.4%) pts enrolled in the trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (determined by Independent Review Committee; IRC) were used for response assessment in 282/633 (44.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 251/282 (89.0%) pts had a CMR, and 213/251 (84.9%) underwent confirmatory BMBs at EOI (203 [95.3%] negative, 5 [2.3%] positive, and 5 [2.3%] indeterminate). Thus, BMB results only affected response by Lugano 2014 in 4.7% of pts having a repeat BMB (0.8% of all enrolled pts). Of 1418 randomized DLBCL pts in GOYA, 167 (11.8%) had a positive (154 pts, 10.9%) or indeterminate (13 pts, 0.9%) baseline BMB; information was missing for 14 pts (1.0%). Bone marrow involvement was prognostic for PFS (INV-assessed PFS: HR 0.75 [95% CI: 0.56, 0.99]; 3-year PFS rate 55.3% vs 69.8% for pts with positive vs non-positive BMBs, respectively). At EOI, 69/167 (41.3%) pts had a CR on CT by IWG criteria, 49 of whom had a follow-up BMB to confirm response; 47/49 (95.9%) had a negative BMB and 2/49 (4.0%) were positive. Therefore, only 2/49 (4.0%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 2/1418 (0.1%) pts enrolled in the GOYA trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (by IRC) were used for response assessment in 121/167 (72.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 96/121 (79.3%) pts had a CMR, and 70/96 (72.9%) underwent confirmatory BMB. Of these, 65/70 (92.9%) were negative. Thus, BMB results only affected response by Lugano 2014 in 7.1% of pts having a repeat BMB (0.4% of all enrolled pts). Conclusions: In previously untreated FL and DLBCL pts in the GALLIUM and GOYA studies, post-induction BMB results impacted the CR rate by IWG criteria in only a minority of pts (<5% of pts with an initial positive/indeterminate BMB and EOI CR by CT who underwent repeat BMB and 0.1-0.4% of all enrolled pts). There was a trend toward similar findings when Lugano 2014 criteria were used, but conclusions are limited because only a subset of pts underwent PET imaging. In design of future FL trials, consideration should be given to eliminating the requirement for BMB to confirm CR. With increasing use of Lugano criteria, particularly in DLBCL, investigations should continue to evaluate the impact of BMBs when PET scans are used to assess response. Disclosures Hiddemann: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research…

Blood, Nov 29, 2018

Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell ... more Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus 6-8 cycles of CHOP (R-CHOP). While the RICOVER trial (Pfreundschuh et al. Lancet Oncol 2008) showed no benefit of 6 versus 8 cycles of R-CHOP administered at 2-weekly intervals, this has not been assessed with the standard 3-weekly regimen, and many centers continue to administer 8 cycles. GOYA (NCT01287741) was an open-label, randomized, Phase III study of the efficacy and safety of R-CHOP versus obinutuzumab (GA101; G) plus CHOP in previously untreated pts with DLBCL. The current exploratory analysis compared investigator (INV)-assessed progression-free survival (PFS) and overall survival (OS) in pts receiving 6 or 8 cycles of CHOP in combination with 8 cycles of R in GOYA. Methods: Eligible pts were aged ≥18 years with histologically documented, CD20-positive DLBCL and ≥1 bi-dimensionally measurable lesion, ECOG PS 0-2, IPI score ≥2, and adequate hematologic function. Low-risk pts with IPI score 1 not due to age alone or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts who were randomized to R-CHOP received 8 cycles of R (375mg/m2) in combination with 6 (CHOP6) or 8 (CHOP8) cycles of CHOP. Centers elected upfront to administer either 6 or 8 CHOP cycles to all pts enrolled at that site. Efficacy was evaluated in all pts who were randomized to R-CHOP (intent-to-treat population; data cut-off: January 31, 2018). Safety was assessed in all pts who completed the 6th treatment cycle and received R in the 7th cycle (CHOP6 safety population: no additional CHOP cycles; CHOP8 safety population: at least 7 or 8 CHOP cycles received). Only AEs starting during or after the 7th cycle were considered. Statistical analyses included Kaplan-Meier estimates and Cox-regression, with and without propensity score adjustment to correct for baseline imbalances. Results: Results are reported for 712 pts who were randomized to R-CHOP (CHOP6, n=526; CHOP8, n=186; safety population: CHOP6, n=461; CHOP8, n=144). In the CHOP6 group, 55% were male and median age was 62 years (range 54-70). In CHOP8, 49% were male and median age was 60 years (range 47-67). Baseline characteristics were broadly comparable across treatment groups, except for geographic region (CHOP6 vs CHOP8: Asia, 32% vs 49%, respectively; Eastern Europe, 10% vs 24%; Western Europe, 36% vs 13%; North America, 18% vs 8%; other, 4% vs 5%). In CHOP6, 89% completed 6 cycles of R-CHOP, while in CHOP8, 76% completed 8 cycles. Three-year INV-assessed PFS rates were comparable between groups: 68.7% in CHOP6 versus 66.8% in CHOP8 (HR 0.92; 95% CI: 0.69, 1.23; Figure 1a). Three-year OS rates appeared higher in the CHOP6 group (83.2% vs 76.2% in CHOP8; HR 0.65; 95% CI: 0.46, 0.91; Figure 1b). PFS and OS comparisons were unchanged after propensity score adjustment for the prespecified baseline characteristics, including age, gender, disease stage, geographic region, IPI score, extranodal sites, body surface area, bulky disease, LDH, and COO (PFS: HR 0.96, 95% CI: 0.70, 1.32; OS: HR 0.66, 95% CI: 0.45, 0.97). Interim treatment response (by CT) did not influence these findings. Model-based subgroup analysis according to baseline pt characteristics did not identify any pt subgroups benefitting from 8 versus 6 cycles of CHOP (Figure 1c). Incidence of grade 3-5 adverse events (AEs) was lower in the CHOP6 group than in the CHOP8 group (17.8% vs 38.9%, respectively); cardiac AEs (all grade: 2.4% vs 6.3%; grade 3-5: 1.3% vs 3.5%) and infections (all grade: 10.6% vs 23.6%) were also less common. In support of these findings, similar results were achieved after repeating the same efficacy analysis in pts who received 6 or 8 cycles of CHOP in combination with 8 cycles of obinutuzumab. Conclusions: In this exploratory analysis of 712 previously untreated DLBCL pts in GOYA, in which the number of CHOP cycles was selected upfront by each site, no additional PFS benefit was observed with 8 cycles of R-CHOP compared with 6 cycles of R-CHOP plus 2 cycles of R, even after adjusting for baseline differences, including COO and IPI. Slow response, assessed by interim CT, did not influence these findings. Furthermore, incidence of grade 3-5 AEs (including cardiac) and any grade infections was markedly higher in pts receiving 8 cycles of CHOP versus 6 cycles. These results suggest that rituximab with 6 cycles of 3-weekly CHOP should be considered standard of care. Disclosures Sehn: Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Culligan:JAZZ: Honoraria; Celgene: Other: Support to attend conferences; Takeda: Honoraria,…

Blood, Nov 5, 2020

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a significant source of cancer morbidity a... more Introduction: Diffuse large B-cell lymphoma (DLBCL) is a significant source of cancer morbidity and mortality. More than half of all newly diagnosed patients are older than 65 years, among whom the 5-year relative survival rate is 54% (SEER 2020). Prior research has shown that not all elderly patients (≥80 years old) receive R-CHOP or mini-R-CHOP regimens as the first line of therapy (LoT); those who do not may have suboptimal outcomes (Williams, et al. Cancer 2015; Hamlin, et al. Oncologist 2014; Juul, et al. Eur J Cancer 2018). This study leverages two real-world data (RWD) sources, Flatiron Health (FH) electronic health record-derived de-identified database and SEER-Medicare (SEER-M) to characterize elderly patients with DLBCL (including observed treatment patterns), summarize overall survival (OS) outcomes, and identify unmet medical needs in this population. Methods: RWD from FH included patients with a DLBCL diagnosis on or after January 1, 2011, with follow-up until May 31, 2020. The SEER-M database is a linkage of two population-based RWD sources: the SEER Cancer Registry and Medicare claims database. RWD from SEER-M for this study included patients with a DLBCL diagnosis between January 1, 2011 and December 31, 2015, with follow-up until December 31, 2016. All fee-for-service Medicare enrollees in SEER-M had to have complete claims. RWD for basic demographics, treatments and outcomes were analyzed from both datasets; FH's database included data on certain clinical characteristics including granularity for dosing data when available, in comparison to SEER-M. This descriptive analysis included patients who were aged ≥80 years at diagnosis. Among patients in the FH database who received R-CHOP as first LoT and had available dosing data, those who received <80% of standard full doses for cyclophosphamide (750mg/m2) and doxorubicin (50mg/m2) at first administration were classified as "reduced-dose" R-CHOP. OS data were summarized using an unadjusted Kaplan-Meier survival function and 95% confidence intervals (CI). Results: The study included 725 patients from the FH database and 2613 patients from the SEER-M database; patient characteristics and outcomes were generally consistent between the two datasets. In total, 16% and 35% of the elderly patients had no record of systemic treatment in FH and SEER-M respectively (Table). More than half of the treated patients received R-CHOP in the first LoT (63% and 53% in FH and SEER-M, respectively); other patients received attenuated regimens, including rituximab plus bendamustine (R-Benda), rituximab plus cyclophosphamide, vincristine and prednisolone (R-CVP), and rituximab (R) monotherapy. Patients who received R-CHOP in the first LoT had numerically longer median OS (Flatiron: 55.0 months [95% CI: 41.8-NA]; SEER-M: 50.7 months [95% CI: 45.9-62.9]) compared with those who received other regimens (Figure A, B). Untreated patients had a median survival of 3.1 months (95% CI: 2.3-5.2) in the Flatiron dataset and 2.0 months (95% CI: 1.8-2.2) in the SEER-M dataset. Among those who received R-CHOP and with available dosing data, 51% received reduced-dose R-CHOP in the first LoT and OS appeared shorter than for patients who received full-dose R-CHOP (Figure C). Conclusions: Despite differences between the databases, RWD in FH and SEER-M both demonstrate considerable variation in the regimens received by elderly DLBCL patients, with 16-35% receiving no treatment and >50% receiving attenuated regimens including reduced-dose R-CHOP. Patients receiving regimens other than R-CHOP had a numerically lower survival probability compared with the standard of care (SoC) R-CHOP/reduced-dose R-CHOP. These data show a high unmet medical need among elderly patients with DLBCL who may not be able to tolerate immunochemotherapy regimens that have been evaluated in trials for a carefully selected patient population. Further research will aim to assess prognostic factors at the time of treatment initiation, as well as gather information on comorbidities and other factors that may prevent elderly patients from receiving SoC R-CHOP; these patients may be candidates for better-tolerated novel approaches. Disclosures Shewade: Genentech, Inc.: Current Employment. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding. Pace:Genentech, Inc.: Current Employment; Exponent: Ended employment in the past 24 months; Prior employer was a consulting firm. No expert testimony given. No relevant consulting work done.: Consultancy. Surinach:Seattle Genetics: Research Funding. Sellam:F. Hoffmann-La Roche: Current Employment. Mueller:Genentech, Inc.: Current Employment, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded…

Blood, Nov 13, 2019

Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is ritu... more Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus CHOP (R-CHOP). However, approximately 35-40% of patients (pts) relapse following such treatment, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 monoclonal antibody. It has demonstrated greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R, and has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in first-line treatment of pts with advanced DLBCL (Sharman et al. Leuk Lymphoma 2019). GOYA (NCT01287741) was a randomized, open-label, multicenter Phase III study that compared the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. In the primary analysis (median observation period: 29 months), G-CHOP did not significantly improve investigator (INV)-assessed progression-free survival (PFS) compared with R-CHOP (Vitolo et al. J Clin Oncol 2017). Here, we present results from the final analysis of GOYA. Methods: Pts were aged ≥18 years, had histologically documented, previously untreated, CD20-positive DLBCL, with adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status of ≤2, and were classified as being in an International Prognostic Index (IPI) risk group of high, high-intermediate, or low-intermediate risk. Low-risk pts with an IPI score of 1 (not due to age alone) or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts were randomized (1:1) to 8 (21-day) cycles of G (1000mg i.v. on Days [D]1, 8 and 15, Cycle [C]1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was INV-assessed PFS. Secondary endpoints included independent review committee-assessed PFS (primary analysis only); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (according to modified Cheson 2007 criteria); event-free survival; disease-free survival; duration of response; time to next anti-lymphoma treatment; PFS according to cell of origin (COO; germinal center B cell [GCB] or activated B cell [ABC]), as an exploratory endpoint; and safety. Results: In total, 1418 pts were randomized in GOYA; of these, 704 pts who received G-CHOP and 710 who received R-CHOP were included in this final analysis (clinical cut-off date: January 31, 2018). Overall median follow-up was 47.7 months. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms. INV-assessed PFS was similar between G-CHOP and R-CHOP (5-year PFS, 63.8% vs 62.6%; stratified HR, 0.94; 95% CI: 0.78, 1.12; p=0.48; Table). There was no significant difference in 5-year OS between the G-CHOP and R-CHOP groups (77.0% vs 77.7%) or in CR or ORR (Table). In the subgroup analysis of pts with ABC, GCB and unclassified DLBCL, no significant reductions in risk of disease progression were observed (stratified HR for INV-PFS, 0.91 [95% CI: 0.61, 1.36], 0.80 [95% CI: 0.58, 1.12] and 1.10 [95% CI: 0.65, 1.88], respectively). No new safety signals were identified. Grade ≥3 adverse events (AEs; 75% vs 66%) and serious AEs (44% vs 38%) were more common with G-CHOP than R-CHOP. Grade ≥3 AEs of particular interest (≥2% of pts in either treatment arm) were more frequent in the G-CHOP arm: infusion-related reactions (10% vs 3%), neutropenia (57% vs 47%), infections (20% vs 16%), cardiac events (5% vs 3%), thrombocytopenia (6% vs 2%), and hemorrhagic events (3% vs 1%); secondary malignancies occurred in 3% and 2% of the R-CHOP and G-CHOP arms, respectively. AEs resulting in treatment withdrawal (12% [87/702] G-CHOP; 8% [58/701] R-CHOP) and AEs with fatal outcome (6% [43/702] G-CHOP; 4% [31/701] R-CHOP) were slightly more common with G-CHOP. The most common grade 5 AEs were pneumonia (n=5 both arms) and sepsis/septic shock (G-CHOP, n=7; R-CHOP, n=3). Conclusions: Consistent with the primary analysis, G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. Furthermore, there was no significant difference in 5-year OS between the treatment arms. No unexpected safety signals were identified. Further investigation of outcomes is ongoing, including the prognostic value of COO and BCL2 positivity. Disclosures Sehn: F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen:…

Blood, Nov 13, 2019

Introduction: Up to 40% of patients (pts) with previously untreated diffuse large B-cell lymphoma... more Introduction: Up to 40% of patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) fail to achieve remission, or relapse, with standard-of-care rituximab (R) plus CHOP (R-CHOP). Atezolizumab (atezo) is a fully humanized anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mode of action to R. We present updated data from an ongoing Phase I/II study (NCT02596971) evaluating the safety and efficacy of atezo combined with R-CHOP (R-CHOP-atezo) in pts with previously untreated DLBCL. This is an updated analysis performed at the end of consolidation (EOC). Methods: This open-label, multicenter study enrolled adults with previously untreated advanced DLBCL (ECOG performance status 0-2). Pts received induction treatment with R-CHOP-atezo (8 x 21-day cycles of R [375mg/m2 i.v. on Day 1 (Cycles 1-8)] and atezo [1200mg i.v. on Day 1 (Cycles 2−8)], and 6 or 8 cycles of CHOP, as determined by the investigator [INV]). Pts who had a complete response (CR) at end of induction (EOI) received consolidation treatment with atezo 1200mg i.v. on Day 1 of Cycles 9─25, every 21 days for 12 months. Pts are followed for 12 months after EOC. Primary endpoints were safety and efficacy as determined by CR rate at EOI by an independent review committee (IRC) using Lugano 2014 criteria (modified to include required confirmation of CR at EOI by biopsy in cases with bone marrow involvement at baseline, and confirmation of a PET-based partial response [PR] by CT-based CR or PR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: As of May 2019, 42 pts had enrolled and received treatment. Of these, 7 pts discontinued study treatment prior to EOI (protocol violation [n=1], adverse event [AE; n=4], progressive disease [PD; n=1] and withdrawn consent [n=1]); 5 more pts discontinued at EOI (PD [n=2] and PR [n=3]). Of 30 pts initiating consolidation treatment, 15 discontinued (AE [n=9], PD [n=3] and withdrawn consent [n=3]). Median observation time was 21.3 (0.7-29.2) months. Key baseline characteristics included: median age, 65 years; International Prognostic Index (IPI) score ≥3, 69%; cell of origin (COO; Nanostring): ABC (34%), GCB (53%), unclassified (12.5%). Among the 40 pts who received at least one dose of atezo, and were therefore evaluable for efficacy at EOI, 31 (77.5%) had a CR and 4 (10%) had a PR by IRC; PD occurred in 2 (5%) pts; 3 (7.5%) were not evaluable. At 6, 12, 18 (EOC) and 24 months, Kaplan-Meier estimates (95% CI) of INV-assessed PFS were 97.4% (82.8, 99.6), 83.6% (67.0, 92.3), 80.6% (63.5, 90.3) and 74.9% (54.3, 87.2), respectively, and those for OS were 100% (not evaluable), 97.5% (83.6, 99.6), 89.8% (75.1, 96.1) and 86.4% (70.0, 94.2), respectively. Kaplan-Meier survival curves for PFS and OS are shown in the Figure. All 42 pts in the safety population experienced ≥1 AE of any grade, with neutropenia (52.4%), constipation (42.9%) and fatigue (40.5%) the most common. Grade 3-4 AEs occurred in 28/42 (67%) pts during induction and 15/30 (50%) pts during consolidation. Hematologic events were the most common grade 3-4 AEs (Table). One fatal AE (unconfirmed progressive multifocal leukoencephalopathy) was reported during follow-up. Overall, 24% of pts had an AE of special interest (AESI). The most common AESIs during induction were lipase increased (n=1), hyperthyroidism (n=1) and amylase increased (n=1), and those during consolidation were lipase increased (n=2), pancreatitis (n=2) and hepatitis (n=2). These events were generally well managed by atezo discontinuation and steroid treatment, and were largely reversible. AEs led to discontinuation of any treatment in 15 (36%) pts. AEs that led to discontinuation of any treatment in ≥1 pt were neutropenia (n=3), lipase increased (n=3) and amylase increased (n=2). Despite a relatively high number of discontinuations due to AEs during consolidation, events were generally manageable and reversible and all pts maintained response at the time of the analysis. Exploratory biomarker data and minimal residual disease data will be presented. Conclusions: The EOI PET-CR response rate and preliminary PFS with R-CHOP-atezo are encouraging and at least comparable to those previously reported for R-CHOP. The overall safety profile of R-CHOP-atezo appears manageable and as expected, with no new safety signals reported with consolidation and no overall increase in toxicity other than immune-mediated events. Disclosures Younes: BMS: Research Funding; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Genentech: Research Funding; Syndax: Research Funding; Xynomics: Consultancy; Biopath: Consultancy; Takeda: Honoraria; Abbvie: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Research Funding. Burke:Celgene:…

Hematological Oncology, Jun 1, 2021

Pediatric Research, Nov 1, 2010

Background and aim: A high standard of communication between staff and parents in the neonatal un... more Background and aim: A high standard of communication between staff and parents in the neonatal unit is a vital part of family centered care. It is essential to the establishment of good working relationships and improves parent-baby bonding. Information provided should be free of medical jargon and presented in a way that parents can easily understand. We aimed to study parents' perception of the quality of communication in the neonatal unit. Method: A twelve point questionnaire was sent by post to the parents of babies admitted to the neonatal unit from August-October 09. Results: A total of 134 parents were approached and 74(55%) responded. Of the responses 50 (68%) were from mothers and 22 (30%) were from both parents. Gestational age ranged from 28-43 weeks (Median 39.5 weeks) and birth weight from 592-5020 grams (Median 3165 grams).

European Journal of Pain, Jul 2, 2012

Background: Evidence indicates that medical and demographic contextual factors (cFs) impact pain ... more Background: Evidence indicates that medical and demographic contextual factors (cFs) impact pain responses in preterm neonates, but the existing evidence is very heterogeneous. Aim: To explore the effect of cFs on pain responses to heel-stick procedures of preterm infants. Methods: This study was a secondary analysis of data collected during a randomized controlled trial examining pain response to nonpharmacological interventions across repeated heel sticks. Five heel sticks across the first 14 days of life were videotaped. Pain response was rated with the Bernese Pain Scale for Neonates (BPSN) by four raters blinded to the heel-stick phases (baseline, heel stick, recovery). Demographic and medical cFs were extracted from medical charts. Mixed single and multiple regression analyses were performed controlling for the intervention group, site and heel-stick phase. Results: Apgar scores at 1 min were negatively associated with behavioural (p = 0.002) BPSN scores, while Apgar scores at 5 min after birth were positively associated with behavioural (p = 0.006) scores. Accumulated number of painful procedures (p = 0.002) and gender (p = 0.02) were positively associated with physiological scores while continuous positive airway pressure CPAP (p = 0.009) and mechanical ventilation (p = 0.005) were negatively associated. Conclusion: Higher exposure to painful procedures, male infants and having CPAP or mechanical ventilation were cFs associated with physiological response. The only variables significantly associated with behavioural BPSN scores were Apgar scores but these relationships were inconsistent.

Acta Paediatrica, May 28, 2013

AimTo compare the influence of three different nonpharmacological interventions on cortical activ... more AimTo compare the influence of three different nonpharmacological interventions on cortical activation, heart rate and peripheral oxygen saturation (SaO2) after heelstick in preterm infants.MethodsTwenty five preterm infants between 24 0/7 and 32 0/7 weeks of gestational age were randomized to either oral sucrose (S), facilitated tucking (FT) or a combination of the two interventions (SFT) prior to five heelsticks each within the first 14 days of life. SaO2, heart rate and oxygenation of the somatosensory cortex, measured by near infrared spectroscopy (NIRS), were analysed.ResultsHundred and twenty five heelsticks were performed. The heart rate increased significantly after heelstick in all three intervention groups (p < 0.004 in all groups). The increase was higher in the FT group compared with the other groups (S: p = 0.007; SFT: p = 0.004). There was no difference among the two groups receiving sucrose (S and SFT; p = 0.87). SaO2 did not change significantly after heelstick in all intervention groups. Near infrared spectroscopy measurements did not show a significant change in the curve but patients in the FT group showed a trend towards higher average oxygenation of the contralateral somatosensory cortex.ConclusionOral sucrose seems to be more effective in reducing reaction to pain than FT. Application of both interventions did not show an additive effect.

Pediatrics, Feb 1, 2012

Preterm infants are exposed to inadequately managed painful procedures during their NICU stay, wh... more Preterm infants are exposed to inadequately managed painful procedures during their NICU stay, which can lead to altered pain responses. Nonpharmacologic approaches are established for the treatment of single painful procedures, but evidence for their effectiveness across time is lacking.

Acta Paediatrica, Jul 6, 2010

There is an impressive body of knowledge on pain management in infants hospitalized in neonatal i... more There is an impressive body of knowledge on pain management in infants hospitalized in neonatal intensive care units. However, deficits in the clinical management of pain in these infants remain. One reason is the gap between research evidence and translation of this knowledge into the clinical setting. This is particularly true for non-pharmacological painrelieving methods. Effective performance of some of these methods requires additional staffing and time. This viewpoint articles describes the clinical challenges associated with implementing 'facilitated tucking'. Although 'facilitated tucking' is described as an efficient method for acute pain relief, the clinical facilitators required to successfully implement such a resource consuming-intervention remain unclear. Conclusion: Translational research on the feasibility of using 'facilitated tucking' in the management of neonatal pain is warranted, including the economic impact of this intervention. Increased manpower costs need to be weighed against the possible long-term economical consequences of pain exposure in infants.

European Journal of Pain, Aug 1, 2011

Major efforts to develop objective measurement tools for neonatal pain assessment have been made.... more Major efforts to develop objective measurement tools for neonatal pain assessment have been made. However, the challenge of measuring pain in neonates remains suggesting that contextual factors (cFs) might alter their responses to pain. Although the role of cFs is increasingly discussed as crucial for pain assessment, they are not well described in the literature and are rarely considered in the clinical setting despite their importance.Aim: To systematically examine studies investigating the impact of cFs on pain response in preterm infants.Method: A literature search was undertaken for the period from 1990 to 2009. Studies reporting the relation between one or more cFs and pain response in preterm infants during a heelstick procedure were considered for inclusion.Results: Twenty‐three studies satisfied inclusion criteria. The studies varied relative to their design, sample, analysis procedures, and variables examined. Six categories of cFs emerged: age, pain exposure, health status, therapeutic interventions, behavioral status, and demographic factors. The examined cFs varied in the strength of their association with pain response, although none were invariably related, as evidenced by contradictory findings. In some cases the inconsistencies appeared attributable to methodological limitations in studies. Behavioral and physiological pain responses were not always in agreement as would be expected.Conclusion: This review supports the influence of some cFs on pain response. However, the results remain inconclusive which may be, in part, related to the heterogeneity of the studies. Contextual factors need further investigation for a better understanding of the magnitude of their effect on pain response.

Blood, Nov 13, 2019

Introduction: Multiple response criteria have been proposed for the assessment of treatment respo... more Introduction: Multiple response criteria have been proposed for the assessment of treatment response in lymphoma patients (pts). The Lugano 2014 criteria have been adopted as the current standard for response assessment in lymphoma (Cheson et al. J Clin Oncol 2014), incorporating 18F fludeoxyglucose (FDG)-positron emission tomography (PET)-computed tomography (CT) into standard staging of FDG-avid lymphomas. For non-FDG avid lymphomas, and when PET is not available, Lugano criteria use bi-dimensional tumor measurements of up to six CT target lesions. The more recently proposed Response Evaluation Criteria in Lymphoma (RECIL) (Younes et al. Annals Oncol 2017) were developed based on the hypothesis that uni-dimensional measurements of up to three target lesions could be used to assess response at a similar level of accuracy to the Lugano criteria. The prognostic value of Lugano 2014 versus RECIL 2017 criteria has not yet been assessed in large clinical trials. We compared the prognostic performance of Lugano and RECIL criteria in pts from the Phase III GOYA study (NCT01287741), which compared the efficacy of obinutuzumab (GA101, G) and rituximab (R) in combination with CHOP (G-CHOP vs R-CHOP) in previously untreated pts with CD20-positive DLBCL. Methods: In the GOYA study, pts were randomized 1:1 to receive either G-CHOP or R-CHOP (stratification factors: number of planned chemotherapy cycles, International Prognostic Index [IPI], and geographic region). FDG-PET scans were mandatory at sites where a PET scanner was available and were performed at screening and 6-8 weeks after the last study treatment. Response was assessed prospectively based on Cheson 2007 criteria and retrospectively according to standard Lugano 2014 criteria. A retrospective analysis based on RECIL 2017 criteria was also performed. Response categories by RECIL criteria were cross-tabulated against those by Lugano criteria. Estimates of the treatment effect were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using stratified log-rank tests. The impact of covariates on PFS and OS were analyzed using a multivariate Cox model. Landmark analyses of PFS and OS according to end of treatment (EoT) complete response (CR)/non-CR status were performed, and the prognostic value of response at EoT was compared for the two methods. Results: Of the 1418 pts (intention-to-treat [ITT] population) in the GOYA study, 1334 had PET data and were evaluable for this analysis. Good agreement between Lugano and RECIL criteria was observed for EoT CR status, with 894/966 (92.5%) pts with a complete metabolic response (CMR) by Lugano classified as CR by RECIL (Table). However, 40/63 (63.5%) pts with progressive metabolic disease (PMD) at EoT according to Lugano criteria had a partial response (PR) or minor response (MR) by RECIL criteria, showing poor agreement for these variables. Of the 43 pts with PMD by Lugano and non-PD by RECIL at EoT, 15 pts had no PFS event by Lugano as assessed by CT and could be considered false positives. Concordance for PFS by CT was high between the two criteria, with a kappa estimate of 0.77 (95% CI: 0.74, 0.80). EoT CR status by RECIL was highly prognostic for PFS (stratified HR, 0.32; 95% CI: 0.25, 0.43; p<0.0001) and OS (stratified HR, 0.26; 95% CI: 0.19, 0.36; p<0.0001), with a similar prognostic performance as the Lugano criteria (PFS HR, 0.31; 95% CI: 0.23, 0.41; p<0.0001). Multivariate analysis confirmed that EoT CR status by RECIL was prognostic for both PFS (HR, 0.18; 95% CI: 0.15, 0.23; p<0.0001) and OS (HR, 0.23; 95% CI: 0.17, 0.32; p<0.0001), independent of the stratification factors (IPI, number of planned CHOP cycles, geographic region). Assessment with RECIL criteria provided similar PFS results to GOYA for the comparison of G- vs R-CHOP (RECIL: HR, 0.95; 95% CI: 0.78, 1.17; p=0.64; GOYA: HR, 0.94; 95% CI: 0.78, 1.12; p=0.47). Conclusions: EoT CR status according to RECIL 2017 criteria showed a high concordance with CMR status by Lugano 2014 criteria and was highly prognostic for PFS and OS in previously untreated DLBCL; however, discordance was seen for the identification of PD by RECIL compared with Lugano criteria. PFS as assessed by CT by RECIL, based on uni-dimensional size measurements of up to three target lesions, showed high concordance with PFS by Lugano criteria, based on bi-dimensional size measurements of up to six target lesions. Table Disclosures Kostakoglu: F. Hoffman-La Roche: Consultancy; Genentech: Consultancy. Martelli:F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria; Servier: Honoraria; F. Hoffman-La Roche, Celgene, Janssen, Sandoz, Novartis, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sehn:Astra Zeneca: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Lundbeck:…

Blood, Dec 7, 2017

Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomog... more Introduction: Quantitative 18fluorodeoxyglucose positron emission tomography (PET)/computed tomography assessment using total metabolic tumor volume (TMTV) and tumor lesion glycolysis (TLG) measurements has been found promising as an objective method to predict survival in diffuse large B-cell lymphoma (DLBCL) patients (pts). However, the methodology for PET-derived metrics is still evolving, and their predictive value is yet to be proven in large-scale, prospective, multicenter studies. We investigated the prognostic value of baseline maximum standardized uptake value (SUVmax), TMTV and TLG for progression-free survival (PFS) in a large pt cohort treated with obinutuzumab (GA101; G) or rituximab (R) combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the Phase 3 GOYA study (NCT01287741; Vitolo et al. J Clin Oncol 2017). Methods: Pts aged ≥18 years, with previously untreated, CD20-positive DLBCL and an International Prognostic Index (IPI) score ≥2 and low-risk pts with IPI scores of 1 (not due to age alone) or 0 (with bulky disease) were randomized 1:1 to receive 8 x 21-day cycles of G (1000mg intravenous [IV] on Days [D] 1, 8, and 15 of Cycle [C] 1 and D1, C2-8) or R (375mg/m2 IV on D1, C1-8) plus 6 or 8 cycles of CHOP. All pts had a baseline and end of treatment (EOT) PET. PET images were segmented using an automated workflow program in MIM software, applying thresholds of 1.5 x liver background and a minimum volume of 1mL to the whole body PET images. The data were analyzed for the overall population and according to germinal center B-cell-like (GCB), unclassified, and activated B-cell-like (ABC) subtypes of DLBCL. TMTV, TLG, and SUVmax were split into 4 categories/levels according to the following quartiles: Q1, <25%; Q2, 25-50%; Q3, 50-75%; and Q4, 75-100%, which were obtained based on their distribution in the available population. The reported hazard ratios (HRs) refer to stratified log-rank tests comparing Q2, Q3, and Q4 to Q1, adjusted for stratification factors of the study: IPI score (low [0-2], intermediate [3], and high [4-5]) and number of planned CHOP cycles (6 or 8). Results: Of 1418 enrolled pts, 1346 had a baseline PET scan and 1334 had detectable lesions. There was no statistical difference in PFS between the treatment arms (G vs R), thus the entire cohort was analyzed as a whole. Results of the predictive value of baseline TMTV for PFS are presented in quartiles in Figure 1, and results of the predictive value of TLG for PFS are presented in quartiles in Figure 2, for the overall PET intent-to-treat population. After a median follow-up of 29 months TMTV and TLG were highly predictive of PFS when comparing Q4 vs Q1: HR=2.21, 95% CI 1.48-3.29, p<0.0001, and HR=1.91, 95% CI 1.28-2.85, p=0.0005, respectively. TMTV was also predictive of overall survival (OS): HR=2.63, 95% CI 1.55-4.46; p<0.0001. However, SUVmax-based prediction of PFS was not statistically significant (HR=0.84, 95% CI 0.57-1.23, p=0.3782). Three-year PFS for pts in TMTV Q1, 2, 3 and 4 was 86% (95% CI 81-89%), 84% (95% CI 78-88%), 78% (95% CI 72-83%) and 66% (95% CI 59-71%), respectively. TMTV also showed a trend for a better prediction of PFS (Figure 3) and OS in pts with the unclassified and ABC DLBCL subtypes when compared with those with the GCB subtype. Conclusions: This large prospective study confirms baseline TMTV and TLG as predictors of PFS and OS in DLBCL after first-line immunochemotherapy, while SUVmax may not be a predictor. Furthermore, TMTV and TLG appear to be better predictors of survival for pts with the unclassified and ABC subtypes of DLBCL than for those pts with the GCB subtype. Further analyses are underway comparing these results with the predictive value of percentage change from baseline to EOT PET, Deauville score-based analysis of EOT PET, and the various molecular DLBCL subtypes. Figure 1 Figure 1. Disclosures Kostakoglu: Roche: Consultancy, Other: GOYA is sponsored by F. Hoffmann-La Roche Ltd. Third-party editorial support, under the direction of Lale Kostakoglu and Denis Sahin, was provided by Helen Cathro of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd. Sehn: Celgene: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria. Chua: Lundbeck: Honoraria; Roche: Honoraria; Seattle Genetics: Honoraria; Gilead Sciences: Honoraria; Merck: Honoraria. Gonzalez-Barca: Gilead: Consultancy; Sandot: Consultancy; Janssen: Speakers Bureau; Roche: Speakers Bureau. Pinto: Millenium Takeda: Research Funding; Gilead: Honoraria; Roche: Honoraria; Bristol Myers Squibb: Honoraria; Merck Sharp Dome: Honoraria; Celgene: Honoraria; Helssin: Honoraria; Mundipharma EDO: Speakers Bureau. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Knapp: Roche: Employment. Mattiello: Roche:…

Blood, Dec 7, 2017

Introduction: Reactivation of hepatitis B virus (HBV) is an identified risk associated with immun... more Introduction: Reactivation of hepatitis B virus (HBV) is an identified risk associated with immunochemotherapy for non-Hodgkin lymphoma (NHL) in patients (pts) with resolved HBV infection. This study aimed to evaluate the risk of HBV reactivation and explore risk factors in NHL pts with resolved HBV infection who received anti-CD20 antibody (obinutuzumab or rituximab)-containing immunochemotherapy in the phase III GOYA and GALLIUM studies (involving pts with previously untreated diffuse large B-cell lymphoma [DLBCL] and indolent NHL, respectively). Methods: Pts were randomized to receive induction with either obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2‒8) or rituximab (375 mg/m2 on day 1 of each cycle) in combination with CHOP (GOYA and GALLIUM), CVP (GALLIUM), or bendamustine (GALLIUM) for 6-8 cycles. In GALLIUM, induction was followed by obinutuzumab or rituximab maintenance. Baseline screening was performed locally for hepatitis B surface antigen (HBsAg) and antibody against hepatitis B core antigen (anti-HBc). Pts positive for HBsAg were excluded, while those with resolved HBV infection (HBsAg-negative but anti-HBc-positive) could be enrolled if they had baseline HBV DNA Results: Of 2797 evaluable pts (GOYA, 1407; GALLIUM, 1390), 326 pts were seropositive for anti-HBc (207 were seropositive for antibodies against HBsAg) and 11 had detectable but non-quantifiable HBV DNA (10 to Conclusions: HBV DNA monitoring-guided preemptive NAT was effective in preventing HBV-related hepatitis during treatment with obinutuzumab- or rituximab-containing immunochemotherapy. Antiviral prophylaxis was effective in preventing HBV reactivation and may be an appropriate option for pts with resolved HBV infection and multiple risk factors. Disclosures Kusumoto: Chugai: Honoraria, Other: GALLIUM and GOYA are sponsored by F. Hoffmann-La Roche Ltd. Third-party medical writing support, under the direction of Shigeru Kusumoto, was provided by Cheryl Wright of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Arcaini: Celgene, Roche, Sandoz: Consultancy; Gilead: Research Funding; Pfizer, Celgene, Bayer, Roche: Membership on an entity9s Board of Directors or advisory committees. Kim: JJ Takeda: Research Funding; Celltrion, Inc: Consultancy, Honoraria; Novartis: Research Funding; Roche: Research Funding; Donga: Research Funding; Mundipharma: Research Funding; Kyowa-Kirin: Research Funding. Peters: Genentech, Merck: Honoraria; Roche: Honoraria. Tanaka: BMS: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; GSK: Honoraria, Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Kuriki: Chugai: Employment. Fingerle-Rowson: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Nielsen: F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ueda: Chugai: Employment. Piper-Lepoutre: Roche: Employment. Sellam: Roche: Employment. Tobinai: Daiichi Sankyo Co., Ltd: Consultancy, Honoraria; AbbVie: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; HUYA Bioscience: Honoraria; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria.

Blood, Nov 29, 2018

Introduction: Clinical trial response assessments for follicular lymphoma (FL) and diffuse large ... more Introduction: Clinical trial response assessments for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) typically mandate bone marrow biopsies (BMBs) at baseline and for confirmation of complete response (CR) as assessed by computed tomography (CT) imaging according to International Working Group (IWG) criteria. BMBs are painful and expensive, and can deter patients (pts) from clinical trial participation. Rutherford et al. (Br J Haematol 2017) suggested that confirmatory BMBs do not impact response assessment in the majority of FL pts treated in clinical trials. We describe the impact of confirmatory BMBs on response in the GALLIUM study (NCT01332968), which randomized previously untreated FL pts to obinutuzumab (G)- or rituximab (R)-chemotherapy (CHOP, CVP, or bendamustine) followed by maintenance with the same antibody in responders, and in the GOYA study (NCT01287741), which randomized previously untreated DLBCL pts to G-CHOP or R-CHOP. Methods: We conducted a retrospective analysis of GALLIUM and GOYA to evaluate the percentage of pts with CR as assessed by CT but with a positive BMB at end of induction (EOI), and the percentage of pts with complete metabolic response (CMR) on positron emission tomography (PET) by Lugano 2014 criteria but with a positive BMB at EOI. Response by PET was an exploratory endpoint and not mandatory. Results: Of 1202 randomized FL pts in GALLIUM, 633 (52.7%) had a positive (613 pts, 51.0%) or indeterminate (20 pts, 1.7%) baseline BMB (data missing for 12 pts, 1.0%). Bone marrow involvement was not prognostic for progression-free survival (PFS; investigator (INV)-assessed PFS: HR 0.99 [95% CI 0.80, 1.23] for pts with positive vs non-positive BMB). At EOI, 209/633 (33%) pts had a CR on CT by IWG criteria, 179 of whom had a follow-up BMB to confirm response; 174/179 (97.2%) had a negative BMB that confirmed CR, 1/179 (0.6%) was positive, and 4/179 (2.2%) were indeterminate. Overall, only 5/179 (2.8%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 5/1202 (0.4%) pts enrolled in the trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (determined by Independent Review Committee; IRC) were used for response assessment in 282/633 (44.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 251/282 (89.0%) pts had a CMR, and 213/251 (84.9%) underwent confirmatory BMBs at EOI (203 [95.3%] negative, 5 [2.3%] positive, and 5 [2.3%] indeterminate). Thus, BMB results only affected response by Lugano 2014 in 4.7% of pts having a repeat BMB (0.8% of all enrolled pts). Of 1418 randomized DLBCL pts in GOYA, 167 (11.8%) had a positive (154 pts, 10.9%) or indeterminate (13 pts, 0.9%) baseline BMB; information was missing for 14 pts (1.0%). Bone marrow involvement was prognostic for PFS (INV-assessed PFS: HR 0.75 [95% CI: 0.56, 0.99]; 3-year PFS rate 55.3% vs 69.8% for pts with positive vs non-positive BMBs, respectively). At EOI, 69/167 (41.3%) pts had a CR on CT by IWG criteria, 49 of whom had a follow-up BMB to confirm response; 47/49 (95.9%) had a negative BMB and 2/49 (4.0%) were positive. Therefore, only 2/49 (4.0%) pts with a positive/indeterminate baseline BMB and EOI CR by CT, or 2/1418 (0.1%) pts enrolled in the GOYA trial, had a repeat BMB result that was relevant for response assessment. Lugano 2014 criteria (by IRC) were used for response assessment in 121/167 (72.5%) pts with positive/indeterminate baseline BMBs and EOI PET scans available; 96/121 (79.3%) pts had a CMR, and 70/96 (72.9%) underwent confirmatory BMB. Of these, 65/70 (92.9%) were negative. Thus, BMB results only affected response by Lugano 2014 in 7.1% of pts having a repeat BMB (0.4% of all enrolled pts). Conclusions: In previously untreated FL and DLBCL pts in the GALLIUM and GOYA studies, post-induction BMB results impacted the CR rate by IWG criteria in only a minority of pts (<5% of pts with an initial positive/indeterminate BMB and EOI CR by CT who underwent repeat BMB and 0.1-0.4% of all enrolled pts). There was a trend toward similar findings when Lugano 2014 criteria were used, but conclusions are limited because only a subset of pts underwent PET imaging. In design of future FL trials, consideration should be given to eliminating the requirement for BMB to confirm CR. With increasing use of Lugano criteria, particularly in DLBCL, investigations should continue to evaluate the impact of BMBs when PET scans are used to assess response. Disclosures Hiddemann: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research…

Blood, Nov 29, 2018

Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell ... more Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus 6-8 cycles of CHOP (R-CHOP). While the RICOVER trial (Pfreundschuh et al. Lancet Oncol 2008) showed no benefit of 6 versus 8 cycles of R-CHOP administered at 2-weekly intervals, this has not been assessed with the standard 3-weekly regimen, and many centers continue to administer 8 cycles. GOYA (NCT01287741) was an open-label, randomized, Phase III study of the efficacy and safety of R-CHOP versus obinutuzumab (GA101; G) plus CHOP in previously untreated pts with DLBCL. The current exploratory analysis compared investigator (INV)-assessed progression-free survival (PFS) and overall survival (OS) in pts receiving 6 or 8 cycles of CHOP in combination with 8 cycles of R in GOYA. Methods: Eligible pts were aged ≥18 years with histologically documented, CD20-positive DLBCL and ≥1 bi-dimensionally measurable lesion, ECOG PS 0-2, IPI score ≥2, and adequate hematologic function. Low-risk pts with IPI score 1 not due to age alone or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts who were randomized to R-CHOP received 8 cycles of R (375mg/m2) in combination with 6 (CHOP6) or 8 (CHOP8) cycles of CHOP. Centers elected upfront to administer either 6 or 8 CHOP cycles to all pts enrolled at that site. Efficacy was evaluated in all pts who were randomized to R-CHOP (intent-to-treat population; data cut-off: January 31, 2018). Safety was assessed in all pts who completed the 6th treatment cycle and received R in the 7th cycle (CHOP6 safety population: no additional CHOP cycles; CHOP8 safety population: at least 7 or 8 CHOP cycles received). Only AEs starting during or after the 7th cycle were considered. Statistical analyses included Kaplan-Meier estimates and Cox-regression, with and without propensity score adjustment to correct for baseline imbalances. Results: Results are reported for 712 pts who were randomized to R-CHOP (CHOP6, n=526; CHOP8, n=186; safety population: CHOP6, n=461; CHOP8, n=144). In the CHOP6 group, 55% were male and median age was 62 years (range 54-70). In CHOP8, 49% were male and median age was 60 years (range 47-67). Baseline characteristics were broadly comparable across treatment groups, except for geographic region (CHOP6 vs CHOP8: Asia, 32% vs 49%, respectively; Eastern Europe, 10% vs 24%; Western Europe, 36% vs 13%; North America, 18% vs 8%; other, 4% vs 5%). In CHOP6, 89% completed 6 cycles of R-CHOP, while in CHOP8, 76% completed 8 cycles. Three-year INV-assessed PFS rates were comparable between groups: 68.7% in CHOP6 versus 66.8% in CHOP8 (HR 0.92; 95% CI: 0.69, 1.23; Figure 1a). Three-year OS rates appeared higher in the CHOP6 group (83.2% vs 76.2% in CHOP8; HR 0.65; 95% CI: 0.46, 0.91; Figure 1b). PFS and OS comparisons were unchanged after propensity score adjustment for the prespecified baseline characteristics, including age, gender, disease stage, geographic region, IPI score, extranodal sites, body surface area, bulky disease, LDH, and COO (PFS: HR 0.96, 95% CI: 0.70, 1.32; OS: HR 0.66, 95% CI: 0.45, 0.97). Interim treatment response (by CT) did not influence these findings. Model-based subgroup analysis according to baseline pt characteristics did not identify any pt subgroups benefitting from 8 versus 6 cycles of CHOP (Figure 1c). Incidence of grade 3-5 adverse events (AEs) was lower in the CHOP6 group than in the CHOP8 group (17.8% vs 38.9%, respectively); cardiac AEs (all grade: 2.4% vs 6.3%; grade 3-5: 1.3% vs 3.5%) and infections (all grade: 10.6% vs 23.6%) were also less common. In support of these findings, similar results were achieved after repeating the same efficacy analysis in pts who received 6 or 8 cycles of CHOP in combination with 8 cycles of obinutuzumab. Conclusions: In this exploratory analysis of 712 previously untreated DLBCL pts in GOYA, in which the number of CHOP cycles was selected upfront by each site, no additional PFS benefit was observed with 8 cycles of R-CHOP compared with 6 cycles of R-CHOP plus 2 cycles of R, even after adjusting for baseline differences, including COO and IPI. Slow response, assessed by interim CT, did not influence these findings. Furthermore, incidence of grade 3-5 AEs (including cardiac) and any grade infections was markedly higher in pts receiving 8 cycles of CHOP versus 6 cycles. These results suggest that rituximab with 6 cycles of 3-weekly CHOP should be considered standard of care. Disclosures Sehn: Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Culligan:JAZZ: Honoraria; Celgene: Other: Support to attend conferences; Takeda: Honoraria,…

Blood, Nov 5, 2020

Introduction: Diffuse large B-cell lymphoma (DLBCL) is a significant source of cancer morbidity a... more Introduction: Diffuse large B-cell lymphoma (DLBCL) is a significant source of cancer morbidity and mortality. More than half of all newly diagnosed patients are older than 65 years, among whom the 5-year relative survival rate is 54% (SEER 2020). Prior research has shown that not all elderly patients (≥80 years old) receive R-CHOP or mini-R-CHOP regimens as the first line of therapy (LoT); those who do not may have suboptimal outcomes (Williams, et al. Cancer 2015; Hamlin, et al. Oncologist 2014; Juul, et al. Eur J Cancer 2018). This study leverages two real-world data (RWD) sources, Flatiron Health (FH) electronic health record-derived de-identified database and SEER-Medicare (SEER-M) to characterize elderly patients with DLBCL (including observed treatment patterns), summarize overall survival (OS) outcomes, and identify unmet medical needs in this population. Methods: RWD from FH included patients with a DLBCL diagnosis on or after January 1, 2011, with follow-up until May 31, 2020. The SEER-M database is a linkage of two population-based RWD sources: the SEER Cancer Registry and Medicare claims database. RWD from SEER-M for this study included patients with a DLBCL diagnosis between January 1, 2011 and December 31, 2015, with follow-up until December 31, 2016. All fee-for-service Medicare enrollees in SEER-M had to have complete claims. RWD for basic demographics, treatments and outcomes were analyzed from both datasets; FH's database included data on certain clinical characteristics including granularity for dosing data when available, in comparison to SEER-M. This descriptive analysis included patients who were aged ≥80 years at diagnosis. Among patients in the FH database who received R-CHOP as first LoT and had available dosing data, those who received <80% of standard full doses for cyclophosphamide (750mg/m2) and doxorubicin (50mg/m2) at first administration were classified as "reduced-dose" R-CHOP. OS data were summarized using an unadjusted Kaplan-Meier survival function and 95% confidence intervals (CI). Results: The study included 725 patients from the FH database and 2613 patients from the SEER-M database; patient characteristics and outcomes were generally consistent between the two datasets. In total, 16% and 35% of the elderly patients had no record of systemic treatment in FH and SEER-M respectively (Table). More than half of the treated patients received R-CHOP in the first LoT (63% and 53% in FH and SEER-M, respectively); other patients received attenuated regimens, including rituximab plus bendamustine (R-Benda), rituximab plus cyclophosphamide, vincristine and prednisolone (R-CVP), and rituximab (R) monotherapy. Patients who received R-CHOP in the first LoT had numerically longer median OS (Flatiron: 55.0 months [95% CI: 41.8-NA]; SEER-M: 50.7 months [95% CI: 45.9-62.9]) compared with those who received other regimens (Figure A, B). Untreated patients had a median survival of 3.1 months (95% CI: 2.3-5.2) in the Flatiron dataset and 2.0 months (95% CI: 1.8-2.2) in the SEER-M dataset. Among those who received R-CHOP and with available dosing data, 51% received reduced-dose R-CHOP in the first LoT and OS appeared shorter than for patients who received full-dose R-CHOP (Figure C). Conclusions: Despite differences between the databases, RWD in FH and SEER-M both demonstrate considerable variation in the regimens received by elderly DLBCL patients, with 16-35% receiving no treatment and >50% receiving attenuated regimens including reduced-dose R-CHOP. Patients receiving regimens other than R-CHOP had a numerically lower survival probability compared with the standard of care (SoC) R-CHOP/reduced-dose R-CHOP. These data show a high unmet medical need among elderly patients with DLBCL who may not be able to tolerate immunochemotherapy regimens that have been evaluated in trials for a carefully selected patient population. Further research will aim to assess prognostic factors at the time of treatment initiation, as well as gather information on comorbidities and other factors that may prevent elderly patients from receiving SoC R-CHOP; these patients may be candidates for better-tolerated novel approaches. Disclosures Shewade: Genentech, Inc.: Current Employment. Olszewski:TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding; Spectrum Pharmaceuticals: Research Funding. Pace:Genentech, Inc.: Current Employment; Exponent: Ended employment in the past 24 months; Prior employer was a consulting firm. No expert testimony given. No relevant consulting work done.: Consultancy. Surinach:Seattle Genetics: Research Funding. Sellam:F. Hoffmann-La Roche: Current Employment. Mueller:Genentech, Inc.: Current Employment, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. O'Hear:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded…

Blood, Nov 13, 2019

Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is ritu... more Introduction: The standard first line treatment for diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus CHOP (R-CHOP). However, approximately 35-40% of patients (pts) relapse following such treatment, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; G) is a fully humanized, glycoengineered, type II anti-CD20 monoclonal antibody. It has demonstrated greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R, and has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in first-line treatment of pts with advanced DLBCL (Sharman et al. Leuk Lymphoma 2019). GOYA (NCT01287741) was a randomized, open-label, multicenter Phase III study that compared the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. In the primary analysis (median observation period: 29 months), G-CHOP did not significantly improve investigator (INV)-assessed progression-free survival (PFS) compared with R-CHOP (Vitolo et al. J Clin Oncol 2017). Here, we present results from the final analysis of GOYA. Methods: Pts were aged ≥18 years, had histologically documented, previously untreated, CD20-positive DLBCL, with adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status of ≤2, and were classified as being in an International Prognostic Index (IPI) risk group of high, high-intermediate, or low-intermediate risk. Low-risk pts with an IPI score of 1 (not due to age alone) or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts were randomized (1:1) to 8 (21-day) cycles of G (1000mg i.v. on Days [D]1, 8 and 15, Cycle [C]1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was INV-assessed PFS. Secondary endpoints included independent review committee-assessed PFS (primary analysis only); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (according to modified Cheson 2007 criteria); event-free survival; disease-free survival; duration of response; time to next anti-lymphoma treatment; PFS according to cell of origin (COO; germinal center B cell [GCB] or activated B cell [ABC]), as an exploratory endpoint; and safety. Results: In total, 1418 pts were randomized in GOYA; of these, 704 pts who received G-CHOP and 710 who received R-CHOP were included in this final analysis (clinical cut-off date: January 31, 2018). Overall median follow-up was 47.7 months. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms. INV-assessed PFS was similar between G-CHOP and R-CHOP (5-year PFS, 63.8% vs 62.6%; stratified HR, 0.94; 95% CI: 0.78, 1.12; p=0.48; Table). There was no significant difference in 5-year OS between the G-CHOP and R-CHOP groups (77.0% vs 77.7%) or in CR or ORR (Table). In the subgroup analysis of pts with ABC, GCB and unclassified DLBCL, no significant reductions in risk of disease progression were observed (stratified HR for INV-PFS, 0.91 [95% CI: 0.61, 1.36], 0.80 [95% CI: 0.58, 1.12] and 1.10 [95% CI: 0.65, 1.88], respectively). No new safety signals were identified. Grade ≥3 adverse events (AEs; 75% vs 66%) and serious AEs (44% vs 38%) were more common with G-CHOP than R-CHOP. Grade ≥3 AEs of particular interest (≥2% of pts in either treatment arm) were more frequent in the G-CHOP arm: infusion-related reactions (10% vs 3%), neutropenia (57% vs 47%), infections (20% vs 16%), cardiac events (5% vs 3%), thrombocytopenia (6% vs 2%), and hemorrhagic events (3% vs 1%); secondary malignancies occurred in 3% and 2% of the R-CHOP and G-CHOP arms, respectively. AEs resulting in treatment withdrawal (12% [87/702] G-CHOP; 8% [58/701] R-CHOP) and AEs with fatal outcome (6% [43/702] G-CHOP; 4% [31/701] R-CHOP) were slightly more common with G-CHOP. The most common grade 5 AEs were pneumonia (n=5 both arms) and sepsis/septic shock (G-CHOP, n=7; R-CHOP, n=3). Conclusions: Consistent with the primary analysis, G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. Furthermore, there was no significant difference in 5-year OS between the treatment arms. No unexpected safety signals were identified. Further investigation of outcomes is ongoing, including the prognostic value of COO and BCL2 positivity. Disclosures Sehn: F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Lundbeck: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen:…

Blood, Nov 13, 2019

Introduction: Up to 40% of patients (pts) with previously untreated diffuse large B-cell lymphoma... more Introduction: Up to 40% of patients (pts) with previously untreated diffuse large B-cell lymphoma (DLBCL) fail to achieve remission, or relapse, with standard-of-care rituximab (R) plus CHOP (R-CHOP). Atezolizumab (atezo) is a fully humanized anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mode of action to R. We present updated data from an ongoing Phase I/II study (NCT02596971) evaluating the safety and efficacy of atezo combined with R-CHOP (R-CHOP-atezo) in pts with previously untreated DLBCL. This is an updated analysis performed at the end of consolidation (EOC). Methods: This open-label, multicenter study enrolled adults with previously untreated advanced DLBCL (ECOG performance status 0-2). Pts received induction treatment with R-CHOP-atezo (8 x 21-day cycles of R [375mg/m2 i.v. on Day 1 (Cycles 1-8)] and atezo [1200mg i.v. on Day 1 (Cycles 2−8)], and 6 or 8 cycles of CHOP, as determined by the investigator [INV]). Pts who had a complete response (CR) at end of induction (EOI) received consolidation treatment with atezo 1200mg i.v. on Day 1 of Cycles 9─25, every 21 days for 12 months. Pts are followed for 12 months after EOC. Primary endpoints were safety and efficacy as determined by CR rate at EOI by an independent review committee (IRC) using Lugano 2014 criteria (modified to include required confirmation of CR at EOI by biopsy in cases with bone marrow involvement at baseline, and confirmation of a PET-based partial response [PR] by CT-based CR or PR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results: As of May 2019, 42 pts had enrolled and received treatment. Of these, 7 pts discontinued study treatment prior to EOI (protocol violation [n=1], adverse event [AE; n=4], progressive disease [PD; n=1] and withdrawn consent [n=1]); 5 more pts discontinued at EOI (PD [n=2] and PR [n=3]). Of 30 pts initiating consolidation treatment, 15 discontinued (AE [n=9], PD [n=3] and withdrawn consent [n=3]). Median observation time was 21.3 (0.7-29.2) months. Key baseline characteristics included: median age, 65 years; International Prognostic Index (IPI) score ≥3, 69%; cell of origin (COO; Nanostring): ABC (34%), GCB (53%), unclassified (12.5%). Among the 40 pts who received at least one dose of atezo, and were therefore evaluable for efficacy at EOI, 31 (77.5%) had a CR and 4 (10%) had a PR by IRC; PD occurred in 2 (5%) pts; 3 (7.5%) were not evaluable. At 6, 12, 18 (EOC) and 24 months, Kaplan-Meier estimates (95% CI) of INV-assessed PFS were 97.4% (82.8, 99.6), 83.6% (67.0, 92.3), 80.6% (63.5, 90.3) and 74.9% (54.3, 87.2), respectively, and those for OS were 100% (not evaluable), 97.5% (83.6, 99.6), 89.8% (75.1, 96.1) and 86.4% (70.0, 94.2), respectively. Kaplan-Meier survival curves for PFS and OS are shown in the Figure. All 42 pts in the safety population experienced ≥1 AE of any grade, with neutropenia (52.4%), constipation (42.9%) and fatigue (40.5%) the most common. Grade 3-4 AEs occurred in 28/42 (67%) pts during induction and 15/30 (50%) pts during consolidation. Hematologic events were the most common grade 3-4 AEs (Table). One fatal AE (unconfirmed progressive multifocal leukoencephalopathy) was reported during follow-up. Overall, 24% of pts had an AE of special interest (AESI). The most common AESIs during induction were lipase increased (n=1), hyperthyroidism (n=1) and amylase increased (n=1), and those during consolidation were lipase increased (n=2), pancreatitis (n=2) and hepatitis (n=2). These events were generally well managed by atezo discontinuation and steroid treatment, and were largely reversible. AEs led to discontinuation of any treatment in 15 (36%) pts. AEs that led to discontinuation of any treatment in ≥1 pt were neutropenia (n=3), lipase increased (n=3) and amylase increased (n=2). Despite a relatively high number of discontinuations due to AEs during consolidation, events were generally manageable and reversible and all pts maintained response at the time of the analysis. Exploratory biomarker data and minimal residual disease data will be presented. Conclusions: The EOI PET-CR response rate and preliminary PFS with R-CHOP-atezo are encouraging and at least comparable to those previously reported for R-CHOP. The overall safety profile of R-CHOP-atezo appears manageable and as expected, with no new safety signals reported with consolidation and no overall increase in toxicity other than immune-mediated events. Disclosures Younes: BMS: Research Funding; Epizyme: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; HCM: Consultancy; Genentech: Research Funding; Syndax: Research Funding; Xynomics: Consultancy; Biopath: Consultancy; Takeda: Honoraria; Abbvie: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Curis: Honoraria, Research Funding; Merck: Honoraria, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Research Funding. Burke:Celgene:…