Total metabolic tumor volume as a survival predictor for patients with diffuse large B-cell lymphoma in the GOYA study

This retrospective analysis of the phase III GOYA study investigated the prognostic value of baseline metabolic tumor volume parameters and maximum standardized uptake values for overall and progression-free survival (PFS) in treatment-naïve diffuse large B-cell lymphoma. Baseline total metabolic tumor volume (determined for tumors >1 mL using a threshold of 1.5 times the mean liver standardized uptake value +2 standard deviations), total lesion glycolysis, and maximum standardized uptake value positron emission tomography data were dichotomized based on receiver operating characteristic analysis and divided into quartiles by baseline population distribution. Of 1,418 enrolled patients, 1,305 had a baseline positron emission tomography scan with detectable lesions. Optimal cut-offs were 366 cm3 for total metabolic tumor volume and 3,004 g for total lesion glycolysis. High total metabolic tumor volume and total lesion glycolysis predicted poorer PFS, with associations retained after adjustment for baseline and disease characteristics (high total metabolic tumor volume hazard ratio: 1.71, 95% confidence interval [CI]: 1.352.18; total lesion glycolysis hazard ratio: 1.46; 95% CI: 1.15-1.86). Total metabolic tumor volume was prognostic for PFS in subgroups with International Prognostic Index scores 0-2 and 3-5, and those with different cell-of-origin subtypes. Maximum standardized uptake value had no prognostic value in this setting. High total metabolic tumor volume associated with high International Prognostic Index or non-germinal center B-cell classification identified the highest-risk cohort for unfavorable prognosis. In conclusion, baseline total metabolic tumor volume and total lesion glycolysis are independent predictors of PFS in patients with diffuse large B-cell lymphoma after first-line immunochemotherapy

End-of-treatment PET/CT predicts PFS and OS in DLBCL after first-line treatment: results from GOYA

GOYA was a randomized phase 3 study comparing obinutuzumab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) vs standard-of-care rituximab plus CHOP in patients with previously untreated diffuse large B-cell lymphoma (DLBCL). This retrospective analysis of GOYA aimed to assess the association between progression-free survival (PFS) and overall survival (OS) with positron emission tomography (PET)-based complete response (CR) status. Overall, 1418 patients were randomly assigned to receive 8 21-day cycles of obinutuzumab (n 5 706) or rituximab (n 5 712) plus 6 or 8 cycles of CHOP. Patients received a mandatory fluoro-2-deoxy-D-glucose-PET/computed tomography scan at baseline and end of treatment. After a median follow-up of 29 months, the numbers of independent review committee-assessed PFS and OS events in the entire cohort were 416 (29.3%) and 252 (17.8%), respectively. End-of-treatment PET CR was highly prognostic for PFS and OS according to Lugano 2014 criteria (PFS: hazard ratio [HR], 0.26; 95% confidence interval [CI], 0.19-0.38; P , .0001; OS: HR, 0.12; 95% CI, 0.08-0.17; P , .0001), irrespective of international prognostic index score and cell of origin. In conclusion, the results from this prospectively acquired large cohort corroborated previously published data from smaller sample sizes showing that end-of-treatment PET CR is an independent predictor of PFS and OS and a promising prognostic marker in DLBCL. Long-term survival analysis confirmed the robustness of these data over time. Additional meta-analyses including other prospective studies are necessary to support the substitution of PET CR for PFS as an effective and practical surrogate end point

Non-pharmacological pain relief interventions and contextual factors influencing pain response in preterm infants : are we measuring what we intend to measure?

Preterm birth is one of the most significant worldwide problems in perinatology. The limited viability of preterm infants have been advanced thanks to the ongoing development of neonatal intensive medicine, although the rates of mortality and morbidity vary according to gestational age. Beside mortality the challenges of preterm birth are associated with short-term morbidity during the neonatal period and moderate to severe long-term morbidity, such as childhood disabilities 1,2 and high financial burdens for the society 1. Preterm infants are spending the first period of their life in a neonatal intensive care unit (NICU), which is critical for their survival. However, this period is characterized by repeated pain exposure, which is occurring during the critical window of central nervous system development 3,4. Recurrent pain exposure during this critical time is associated with permanent changes in peripheral, spinal and supraspinal pain processing, neuroendocrine function and neurologic development 5,6. Furthermore, these changes can be manifested by alterations in pain thresholds, stress responses, cognitive function, behavioral disorders, and long-term disabilities in learning and dampened behavioral pain response 4,7-19. This information brought the pain expert community to recognition that efficient pain management in this population is critical for their future development. The average number of painful procedures preterm infants are exposed to in a NICU stands on +14 procedures per day 20-22, while most of these procedures being associated with minor to moderate pain. While pharmacological pain relief agents are appropriate for severe pain management, they are not adequate to manage minor and routine painful procedures such as heel-stick 20. Furthermore, most of pain medications used for preterm infants in NICUs are off-label or unlicensed for use in this population 23. Therefore, non-pharmacological pain relief interventions are proposed to overcome these challenges. These interventions include methods that involve reducing the sensitivity of the neonates during and after minor painful procedures (e.g. sucrose, non-nutritive sucking, kangaroo care, and facilitated tucking) 24,25. A number of studies have reported the efficacy of non-pharmacological pain relief interventions. Most of these studies, however, examined single painful events. Information is lacking regarding the comparative effectiveness of these interventions and their efficacy over time. In order to provide a basis for efficient pain management, comprehensive pain assessment is required. Pain assessment has gone through major development in the past decades 26, with more than two-dozen pain assessment instruments developed and evaluated. The recommendation is for comprehensive multidimensional assessment method, which include both behavioral (cry, facial expression) and physiological (heart rate, oxygen saturation) measures 27. Despite the major advances in pain assessment in neonates, challenges in understanding the behavior of pain in preterm infants remain. Pain response in preterm infants is variable within and between infants 22,28, and weak correlations are repeatedly reported between behavioral and physiological responses 28-30, which makes clinical interpretation of pain scores difficult. These phenomenon reinforce the belief that pain response in these vulnerable infants seems to involve more than the invasive procedure itself but is further influenced by demographic and medical contextual factors 20,22-24,45. In the past years the scientific pain expert community has widely recognized the issue of contextual factors associated with pain response. The results in the existing literature indicate that the contextual factors consistently associated most with pain responses of preterm infants are age related factors 31-40, previous pain exposure 15,31,34-36,39,41,42, and severity of illness 15,30,34-36,41-43. However, findings even in relation to these contextual factors are not consistent across studies. One explanation for this inconsistency is the varying methodological approaches used in these studies. Therefore, further research is needed to determine which contextual factors are most strongly associated with pain response and to progress one step further with more comprehensive pain assessment instruments. The overall purpose of this project was to compare the effectiveness of two non-pharmacological pain relief interventions over time, and to explore the association between medical and demographic contextual factors and pain response of preterm infants under the impact of non-pharmacological pain relief interventions during repeated routine heel-stick procedures. This thesis includes 7 chapters: Chapter I presents a comprehensive introduction into the relevance of pain in neonates, particularly in preterm infants. The chapter gives an overview of the problem of premature neonatal pain within the context of neurologic development in preterm infants. This leads to the issue of the serious short and long-term consequences of high pain exposure during the neonatal period. The challenges in pain assessment are described within the complexity of the neonatal pain experience in the NICU, leading to the importance of pain management with non-pharmacological pain relief interventions. The last part of the introduction presents the theoretical framework this study was based on. Chapter II describes the specific aims of the dissertation. Chapter III presents a publication of the results of the parent study PAMINA (PAin Management In NeonAtes). PAMINA is multicenter randomized control trial (RCT) that aimed to compare the effectiveness of non-pharmacological pain relief interventions; oral sucrose and facilitated tucking, across 5 heel-stick procedures in preterm infants aged between 24 and 32 weeks of gestation. Seventy-one infants were randomly allocated to one of three interventions: sucrose, facilitated tucking, or the combination of both interventions. Four experienced nurses, blinded to the phase of the heel-stick (baseline, heel-stick, and recovery) assessed pain with the Bernese Pain Scale for Neonates (BPSN). The results show that sucrose with and without facilitated tucking had pain-relieving effects even in preterm infants younger than 32 weeks of gestation and remained effective across time. Chapter IV presents the publication of a commentary article about the intervention of facilitated tucking. In this manuscript we raise the question of the clinical feasibility of facilitated tucking, which requires additional manpower. In light of economic restraints of the health care system, and the lower effectiveness of facilitated tucking compared to sucrose, this commentary encourages re-evaluating the recommendations regarding methods such as facilitated tucking and further recommending for comparative effectiveness studies of non-pharmacological pain relief interventions. Chapter V presents the results of a systematic review, which examined studies investigating the impact of contextual factors on pain response of heel-stick procedures in preterm infants. A total of 23 studies meeting inclusion criteria were included in the review. The studies varied relative to their design, sample, analysis procedures, and variables examined. Six categories of contextual factors emerged: age, pain exposure, health status, therapeutic interventions, behavioral status, and demographic factors. The review supports the influence of some contextual factors on pain response with the factors most consistently related to pain response being age related factors, previous pain exposure and severity of illness. The examined contextual factors varied in the strength of their association with pain response, and none were consistently related, as evidenced by contradictory findings. In some cases the inconsistencies appeared attributable to the methodological heterogeneity of the studies included in the review. The results of the review also support the low correlation between behavioral and physiological pain responses, and the need for further investigation of contextual factors, to better understand their influence on pain response. Chapter VI presents the results manuscript of the exploratory sub analysis of the PAMINA study. This study aimed to explore the association of contextual factors with pain response of preterm infants receiving non-pharmacological interventions for repeated heel-stick procedures. In total 10 demographic and medical CFs were extracted from medical charts over the first 14 days of life. In this study we confirmed the low correlation between behavioral and physiologic pain scores in preterm infants. The results of the study emphasize that higher exposure to painful procedures; male infants and having CPAP or mechanical ventilation were the contextual factors associated with physiological responses. The only variables that were significantly associated with the behavioral scores of the Bernese Pain Scale for Neonates, were Apgar scores at 1 and 5 minutes, however these relationships were inconsistent. In this study we examined a variety of contextual factors that previous studies have suggested may influence preterm infants' pain responses. The use of multivariate analysis while controlling for potential confounders allowed us to examine the independent contribution of each examined contextual factor in explaining pain responses. Furthermore, we utilized a pain assessment instrument that allowed us to examine the impact of the contextual factors on both behavioral and physiologic pain responses. Our findings also add to the growing body of research that suggests the need to considering contextual factors when assessing pain in this population. However, given that findings about the impact of CFs are mixed across studies, additional multicenter research including large sample is needed to determine the contextual factors that need to be incorporated into pain assessment instruments. Finally in Chapter VII the results of all study parts are synthesized and discussed, followed by suggestions for further research and clinical practice development. Pain assessment and management remains a major challenge in preterm infants. The findings of this dissertation support the efficacy of sucrose over time and recommend it over facilitated tucking. While our findings support the importance of considering contextual factors as influencing pain responses in this vulnerable population, the specific contextual factors that need to be incorporated into pain assessment scales remains unclear. Our findings raise important methodological issues that need to be considered as future studies are designed to examine the impact of contextual factors on pain responses of preterm infants

Physiological parameters after nonpharmacological analgesia in preterm infants: a randomized trial

To compare the influence of three different nonpharmacological interventions on cortical activation, heart rate and peripheral oxygen saturation (SaO2 ) after heelstick in preterm infants.; Twenty 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.; Hundred 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.; Oral sucrose seems to be more effective in reducing reaction to pain than FT. Application of both interventions did not show an additive effect

Oral sucrose and "facilitated tucking" for repeated pain relief in preterms: a randomized controlled trial

To test the comparative effectiveness of 2 nonpharmacologic pain-relieving interventions administered alone or in combination across time for repeated heel sticks in preterm infants

A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA

Background: Rituximab (R) plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the current standard therapy for diffuse large B cell lymphoma (DLBCL). Obinutuzumab (G), a glycoengineered, type II anti-CD20 monoclonal antibody, has shown activity and an acceptable safety profile when combined with CHOP (G-CHOP) in patients with advanced DLBCL. We present the final analysis results of the Phase III GOYA study (NCT01287741), which compared the efficacy and safety of G-CHOP versus R-CHOP in patients with previously untreated DLBCL. Methods: Patients aged ≥ 18 years with previously untreated advanced DLBCL were randomly assigned to receive eight 21-day cycles of R or G, plus six or eight cycles of CHOP. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival, other time-to-event endpoints, and safety; investigator-assessed PFS by cell of origin subgroup was an exploratory endpoint. Results: A total of 1418 patients were randomized, with 1414 included in this final analysis (G-CHOP, N = 704; R-CHOP, N = 710). Five-year PFS rates were 63.8% and 62.6% for G-CHOP and R-CHOP, respectively (stratified hazard ratio 0.94, 95% CI 0.78–1.12; p = 0.48). The results of the secondary efficacy endpoints did not show a benefit of G-CHOP over R-CHOP. In the exploratory analysis, a trend towards benefit with G-CHOP over R-CHOP was apparent in the patients with germinal center B cell DLBCL. The safety profile of G-CHOP was as expected, and no new safety signals were observed. More grade 3–5 (75.1% vs 65.8%), serious (44.4% vs 38.4%), and fatal (6.1% vs 4.4%) adverse events (AEs) were observed in the G-CHOP arm compared with the R-CHOP arm, respectively, with the most common fatal AEs being infections. A higher incidence of late-onset neutropenia occurred in the G-CHOP arm (8.7%) versus the R-CHOP arm (4.9%). Conclusions: The final analysis, similar to the primary analysis, did not show a PFS benefit of G-CHOP over R-CHOP in previously untreated patients with DLBCL. The results of the secondary endpoints were consistent with the primary endpoint. Further exploratory analyses and investigation of biomarkers are ongoing.Other UBCNon UBCReviewedFacult

Anti-CD20-atezolizumab-polatuzumab vedotin in relapsed/refractory follicular and diffuse large B-cell lymphoma

Purpose New therapies are needed for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. This phase 1b, open-label trial evaluated two anti-CD20-based triplet combinations. Methods Patients with R/R follicular lymphoma (FL; n = 13) were treated with obinutuzumab, atezolizumab, and polatuzumab vedotin (G-atezo-pola; 1.4 mg/kg/1.8 mg/kg) and patients with R/R diffuse large B-cell lymphoma (DLBCL; n = 23) received rituximab (R)-atezo-pola. The primary efficacy endpoint was complete response (CR) at end of induction (EOI) by PET-CT (investigator assessed; modified Lugano 2014 criteria). Safety endpoints were also assessed. Results 13 FL patients were treated and evaluable for safety; 2/23 DLBCL patients did not receive treatment and were not included in the safety population. Median observation time was 23.3 and 5.7 months in the FL and DLBCL cohorts, respectively. At EOI, CR rates in FL patients treated with G-atezo-pola at pola doses of 1.4 mg/kg (N = 3) and 1.8 mg/kg (N = 7) were 33% and 14%, respectively. In DLBCL patients receiving R-atezo-pola, the CR rate at EOI was 13%. In the FL cohort, 62% of patients experienced a grade 3-5 adverse event (AE; including two deaths) and 31% developed a serious AE (SAE). In DLBCL patients, R-atezo-pola was associated with a lower incidence of grade 3-5 AEs (24%; one death) and SAEs (10%). In both cohorts, the most common grade 3-5 AEs were hematologic toxicities. Conclusion Based on these safety issues, considered as related specifically to G-atezo-pola, and limited efficacy, no further development of either combination is planned

Safety and Efficacy of Atezolizumab in Combination with Rituximab Plus CHOP in Previously Untreated Patients with Diffuse Large B-Cell Lymphoma (DLBCL): Primary Analysis of a Phase I/II Study

Abstract Introduction: Rituximab (R) plus CHOP (R-CHOP) is standard of care for patients (pts) with previously untreated DLBCL. Although most pts have long-term responses, up to 40% of pts fail to achieve a remission or relapse. Atezolizumab (atezo) is a fully humanized anti-programmed death-ligand 1 (PD-L1) antibody with a complementary mechanism of action to R. An ongoing Phase I/II study (NCT02596971) is evaluating the safety and efficacy of atezo in combination with R-CHOP (R-CHOP-atezo) in DLBCL pts. Results from the primary analysis are reported. Methods: This open-label, multicenter study enrolled pts (≥18 years; ECOG PS 0-2) with previously untreated advanced DLBCL (Ann Arbor Stage III/IV, International Prognostic Index [IPI] score ≥2 or Stage II with bulky disease [at least 1 lesion ≥7cm]). Pts received induction treatment with R-CHOP-atezo (8 cycles [each 21 days] of R [375mg/m2 IV on Day 1 (Cycles 1-8)] and atezo [1200mg IV on Day 1 (Cycles 2−8)], and 6 or 8 cycles of CHOP [as determined by the investigator (INV)]). Pts who achieved a complete response (CR) at end of induction (EOI) received consolidation treatment with atezo 1200mg IV on Day 1 of Cycles 9─25, every 21 days for 12 months (mo). Primary endpoints were safety, and efficacy as determined by CR rate at EOI by independent review committee (IRC) using modified Lugano 2014 criteria (if bone marrow [BM] involvement at baseline [BL], CR was confirmed with a negative BM biopsy at EOI; designation of partial response [PR] on PET required that CR or PR on CT scan were met). Secondary endpoints included CR at EOI assessed by INV (modified Lugano 2014 criteria) and by IRC and INV (Cheson et al. J Clin Oncol 2007). Minimal residual disease (MRD) was evaluated at EOI using the Adaptive ImmunoSEQ® NGS platform (v2). Results: At the data cut-off (April 11, 2018), 42 pts were enrolled and received treatment (safety population); 7 pts discontinued during the induction phase (1 protocol violation, 1 withdrawal of consent [these 2 pts discontinued after Cycle 1, Day 1 and were not treated with atezo, and were not included in the efficacy analysis], 4 adverse events [AEs], 1 progressive disease [PD]). Of 35 pts completing induction, 30 entered the consolidation phase; 5 pts discontinued at EOI (2 PD, 3 PR). Pt demographics and disease characteristics are shown in Table 1. Among 40 pts evaluable for response (efficacy population), 31 pts (77.5%) had a CR and 4 pts (10%) had a PR by IRC (modified Lugano 2014 criteria); PD occurred in 2 pts (5%), and 3 pts (7.5%) were not evaluable. Response assessments by Cheson et al. (J Clin Oncol 2007) were similar by IRC and INV; IRC assessment showed 31 (77.5%) CRs, 5 (12.5%) PRs, 2 (5%) pts with PD and 1 with SD (Table 2). MRD was evaluable in 26 pts at BL: 10 pts were MRD negative and 16 pts were MRD positive. Of the 16 MRD positive pts at BL, MRD data were available for 14 at EOI: 13 pts were negative and 1 pt was positive (PR by INV and IRC). Median dose intensity was >99% for the induction phase (median exposure 6.7 mo [range 1.5-7.3]) and 100% for the consolidation phase (median exposure 3.7 mo [range 0.7-9.3]). During induction, all 42 pts (100%) had ≥1 AE, 29 (69%) had a grade (Gr) 3-4 AE and 12 (29%) had a serious AE. No fatal AEs were reported. AEs led to any treatment discontinuation in 6 pts (14%) (Gr 3 neutropenia and Gr 3 transaminase increase, Gr 2 hyperthyroidism, Gr 3 lipase increase, Gr 1-2 peripheral neuropathy, Gr 4 thrombocytopenia), dose reduction (CHOP) in 9 pts (21%) (Gr 4 anemia, Gr 3 pancytopenia, Gr 2 paresthesia, Gr 4 neutropenia and Gr 1-2 peripheral neuropathy) and dose interruption (missed doses and dose delays) in 15 pts (36%). Five pts had AEs of interest to atezo (Gr 3 increased lipase, Gr 2 hyperthyroidism, and Gr 1 infusion-related reaction). Common Gr 3-4 AEs during induction were: neutropenia (45%), febrile neutropenia (9.5%), leukopenia (5%), anemia (5%), increased lipase (5%), and fatigue (5%), and during consolidation were: neutropenia (10%), febrile neutropenia (3%), increased lipase (14%), and syncope (7%). Conclusions: The PET-CR rate with R-CHOP-atezo at EOI is encouraging and compares favorably with that previously reported with R-CHOP. The overall safety profile of R-CHOP-atezo is manageable, with no new safety signals reported. Preliminary MRD data at EOI are encouraging and support activity. Biomarker data and duration of response will be presented. Disclosures Younes: Sanofi: Honoraria; Roche: Honoraria, Research Funding; Takeda: Honoraria; Bayer: Honoraria; J&J: Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Celgene: Honoraria; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Honoraria; Janssen: Honoraria, Research Funding; Abbvie: Honoraria; Genentech: Research Funding; Incyte: Honoraria; Merck: Honoraria; Curis: Research Funding. Burke:Tempus Labs: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau. Cheson:AbbVie, Roche/Genentech, Pharmacyclics, Acerta, TG Therapeutics: Consultancy. Diefenbach:Genentech: Consultancy; Trillium: Research Funding; Millenium/Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding. Hawkes:Celgene: Other: Advisory board, Research Funding; Astra Zeneca: Research Funding; Merck: Other: Advisory board; Takeda: Other: Speaker fee; Roche: Other: Speaker fee; advisory board; Bristol Myers Squibb: Other: Speaker fee, Research Funding; Merck Sharpe Dohme: Research Funding; Merck KGA: Research Funding. Khan:Roche: Honoraria; AbbVie: Honoraria. Lossos:Affimed: Research Funding. Vitolo:Takeda: Speakers Bureau; Gilead: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yuen:Seattle Genetics: Research Funding. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Chitra:Genentech/Roche: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sellam:Roche: Employment. Sharman:Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; Acerta: Consultancy, Research Funding