Biomarkers of outcome in patients undergoing CD19 CAR-T therapy for large B cell lymphoma.

CD19-directed autologous chimeric antigen receptor T cell (CAR-T) therapy has transformed the management of relapsed/refractory (R/R) large B cell lymphoma (LBCL). Initially approved in the third line and beyond setting, CAR-T is now standard of care (SOC) for second-line treatment in patients with refractory disease or early relapse (progression within 12 months) following primary chemoimmunotherapy. Despite becoming SOC, most patients do not achieve complete response, and long-term cure is only observed in approximately 40% of patients. Accordingly, there is an urgent need to better understand the mechanisms of treatment failure and to identify patients that are unlikely to benefit from SOC CAR-T. The field needs robust biomarkers to predict treatment outcome, as better understanding of prognostic factors and mechanisms of resistance can inform on the design of novel treatment approaches for patients predicted to respond poorly to SOC CAR-T. This review aims to provide a comprehensive overview of clinical, molecular, imaging, and cellular features that have been shown to influence outcomes of CAR-T therapy in patients with R/R LBCL.

Temporal Trends of Enrollment by Sex and Race in Major Cardiovascular Randomized Clinical Trials.

Background: Women and racialized minorities continue to be underrepresented in cardiovascular (CV) trial outcomes data, despite comprising a significant global burden of CV disease. This study evaluated the impact of trial characteristics on the temporal enrollment of women and racialized minorities in prominent CV trials published in the period 1986-2023. Methods: MEDLINE was searched for CV trials published in The Lancet, the Journal of the American Medical Association, and the New England Journal of Medicine. Participant and investigator demographics, types of interventions, clinical indications, and funding sources were compared according to the enrollment of women or racialized minorities. Results: From 799 studies, including 4,071,921 patients, the enrollment of women and racialized minorities significantly increased from 1986 to 2023 (both P ≤ 0.001). Although the enrollment of women varied by trial indication, comprising 25.0% of coronary artery disease, 35.2% of noncoronary and/or vascular disease, 13.8% of heart failure, 17.0% of arrhythmia, and 28.7% of other CV trials (P ≤ 0.001), it did not differ by peer-reviewed vs industry funding. First authors who were women were more likely than first authors who were men to enroll significantly more women (P = 0.01). Conclusions: Active efforts to increase diverse enrollment, along with improved reporting, including of sex and race, in future CV trials may increase the generalizability of their findings and applicability to global populations.

Contexte: Les femmes et les groupes racisés demeurent sous-représentés dans les données de résultats d'essais cliniques sur les maladies cardiovasculaires (CV) malgré l'important fardeau global associé à ces maladies. Cette étude visait à évaluer l'effet des caractéristiques des essais sur la sélection temporelle des femmes et des membres de groupes racisés dans les essais portant principalement sur les maladies CV durant la période de 1986 à 2023. Méthodologie: La base de données MEDLINE a été consultée à la recherche d'essais sur les maladies CV publiés dans The Lancet, Journal of the American Medical Association et New England Journal of Medicine. Les données démographiques des participants et des chercheurs, les types d'interventions, les indications cliniques et les sources de financement ont été comparés en fonction de la sélection des femmes ou des membres de groupes racisés. Résultats: Dans 799 études cumulant 4 071 921 patients, la sélection des femmes et des membres de groupes racisés a augmenté significativement entre 1986 et 2023 (p ≤ 0,001 dans les deux cas). Bien que la sélection des femmes variait en fonction des indications des essais, soit 25,0 % dans les essais portant sur les coronaropathies, 35,2 % pour les maladies non coronariennes et/ou vasculaires, 13,8 % pour l'insuffisance cardiaque, 17,0 % pour l'arythmie et 28,7 % pour d'autres maladies CV (p ≤ 0,001), elle ne différait pas selon que les études étaient révisées par des pairs ou qu'elles étaient financées par l'industrie. Lorsqu'une femme était l'autrice principale, le nombre de femmes sélectionnées était susceptible d'être plus élevé que lorsque l'auteur principal était un homme (p = 0,01). Conclusions: Des efforts actifs pour diversifier davantage la sélection des participants et mieux rendre compte des différences, notamment en ce qui concerne le sexe et la race, pourraient élargir la portée des conclusions des futurs essais sur les maladies CV et leur application à l'ensemble de la population.

Indolent lymphoma care delivery and outcomes during the COVID-19 pandemic in Ontario, Canada.

The treatment pattern and outcomes in patients with indolent B-cell lymphoma treated during the coronavirus disease 2019 (COVID-19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population-based study using administrative databases in Ontario, Canada (follow-up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS-CoV-2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2-year course (aHR 0.81, 95% CI 0.71-0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57-0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID-19 complications. Despite similar front-line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort.

Comparative effectiveness of salvage chemotherapy regimens and chimeric antigen T-cell receptor therapies in relapsed and refractory diffuse large B cell lymphoma: a network meta-analysis of clinical trials.

The optimal salvage chemotherapy regimen (SC) for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) prior to autologous stem cell transplant remains unclear. Moreover, although chimeric antigen receptor T cell (CAR-T) therapies were recently approved for primary refractory DLBCL, head-to-head comparisons are lacking. We searched MEDLINE, EMBASE and CENTRAL to July 2022, for randomized trials that enrolled adult patients with R/R DLBCL and performed network meta-analyses (NMA) to assess the efficacy of SC and CAR-T therapies. NMA of SC (6 trials, 7 regimens, n = 1831) indicated that rituximab with gemcitabine, dexamethasone, cisplatin (R-GDP) improved OS and PFS over compared regimens. NMA of 3 CAR-T trials (n = 865) indicated that both axi-cel and liso-cel improved PFS over standard of care, with no difference in OS. Our results indicate that R-GDP may be preferred for R/R DLBCL over other SC compared. Longer follow-up is required for ongoing comparative survival analysis as data from CAR-T trials matures.

Mortality among patients with diffuse large B-cell lymphoma and mental disorders: a population-based study.

BACKGROUND: Mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), but studies examining their association with mortality are lacking. METHODS: We conducted a population-based study using linked administrative health-care databases from Ontario, Canada. All patients with DLBCL 18 years of age or older treated with rituximab-based therapy between January 1, 2005, and December 31, 2017, were identified and followed until March 1, 2020. Mental disorders were defined as either preexisting or postdiagnosis (after lymphoma treatment initiation). Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) between mental disorders and 1-year and all-cause mortality while controlling for covariates. RESULTS: We identified 10 299 patients with DLBCL. The median age of the cohort was 67 years; 46% of patients were female, and 28% had a preexisting mental disorder. At 1-year follow-up, 892 (9%) had a postdiagnosis mental disorder, and a total of 2008 (20%) patients died. Preexisting mental disorders were not associated with 1-year mortality (adjusted HR = 1.06, 95% confidence interval [CI] = 0.96 to 1.17, P = .25), but postdiagnosis disorders were (adjusted HR = 1.51, 95% CI = 1.26 to 1.82, P = .0001). During a median follow-up of 5.2 years, 2111 (22%) patients had a postdiagnosis mental disorder, and 4084 (40%) patients died. Both preexisting and postdiagnosis mental disorders were associated with worse all-cause mortality (preexisting adjusted HR = 1.12, 95% CI = 1.04 to 1.20, P = .0024; postdiagnosis adjusted HR = 1.63, 95% CI = 1.49 to 1.79, P < .0001). CONCLUSIONS: Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with postdiagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality.

Fracture risk among patients with cancer compared to individuals without cancer: a population-based study.

BACKGROUND: Patients with cancer may be at increased risk of osteoporosis and fracture; however, gaps exist in the existing literature and the association between cancer and fracture requires further examination. METHODS: We conducted a population-based cohort study of Ontario patients with cancer (breast, prostate, lung, gastrointestinal, haematologic) diagnosed between January 2007 to December 2018 and 1:1 matched non-cancer controls. The primary outcome was incident fracture (end of follow-up December 2019). Multivariable Cox regression analysis was used to estimate the relative fracture risk with sensitivity analysis accounting for competing risk of death. RESULTS: Among 172,963 cancer patients with non-cancer controls, 70.6% of patients with cancer were <65 years old, 58% were female, and 9375 and 8141 fracture events were observed in the cancer and non-cancer group, respectively (median follow-up 6.5 years). Compared to non-cancer controls, patients with cancer had higher risk of fracture (adjusted HR [aHR] 1.10, 95% CI 1.07-1.14, p < 0.0001), which was also observed for both solid (aHR 1.09, 95% CI 1.05-1.13, p < 0.0001) and haematologic cancers (aHR 1.20, 95% CI 1.10-1.31, p < 0.0001). Sensitivity analysis accounting for competing risk of death did not change these findings. CONCLUSIONS: Our study indicates that patients with cancer are at modest risk of fractures compared to non-cancer controls.

Association of COVID-19 Vaccination With Breakthrough Infections and Complications in Patients With Cancer.

Importance: Patients with cancer are known to have increased risk of COVID-19 complications, including death. Objective: To determine the association of COVID-19 vaccination with breakthrough infections and complications in patients with cancer compared to noncancer controls. Design, Setting, and Participants: Retrospective population-based cohort study using linked administrative databases in Ontario, Canada, in residents 18 years and older who received COVID-19 vaccination. Three matched groups were identified (based on age, sex, type of vaccine, date of vaccine): 1:4 match for patients with hematologic and solid cancer to noncancer controls (hematologic and solid cancers separately analyzed), 1:1 match between patients with hematologic and patients with solid cancer. Exposures: Cancer diagnosis. Main Outcomes and Measures: Outcomes occurring 14 days after receipt of second COVID-19 vaccination dose: primary outcome was SARS-CoV-2 breakthrough infection; secondary outcomes were emergency department visit, hospitalization, and death within 4 weeks of SARS-CoV-2 infection (end of follow-up March 31, 2022). Multivariable cumulative incidence function models were used to obtain adjusted hazard ratio (aHR) and 95% CIs. Results: A total of 289 400 vaccinated patients with cancer (39 880 hematologic; 249 520 solid) with 1 157 600 matched noncancer controls were identified; the cohort was 65.4% female, and mean (SD) age was 66 (14.0) years. SARS-CoV-2 breakthrough infection was higher in patients with hematologic cancer (aHR, 1.33; 95% CI, 1.20-1.46; P < .001) but not in patients with solid cancer (aHR, 1.00; 95% CI, 0.96-1.05; P = .87). COVID-19 severe outcomes (composite of hospitalization and death) were significantly higher in patients with cancer compared to patients without cancer (aHR, 1.52; 95% CI, 1.42-1.63; P < .001). Risk of severe outcomes was higher among patients with hematologic cancer (aHR, 2.51; 95% CI, 2.21-2.85; P < .001) than patients with solid cancer (aHR, 1.43; 95% CI, 1.24-1.64; P < .001). Patients receiving active treatment had a further heightened risk for COVID-19 severe outcomes, particularly those who received anti-CD20 therapy. Third vaccination dose was associated with lower infection and COVID-19 complications, except for patients receiving anti-CD20 therapy. Conclusions and Relevance: In this large population-based cohort study, patients with cancer had greater risk of SARS-CoV-2 infection and worse outcomes than patients without cancer, and the risk was highest for patients with hematologic cancer and any patients with cancer receiving active treatment. Triple vaccination was associated with lower risk of poor outcomes.

Left atrial volume and function measured by cardiac magnetic resonance imaging as predictors of shocks and mortality in patients with implantable cardioverter-defibrillators.

Left atrial (LA) volume and function (LA ejection fraction, LAEF) have demonstrated prognostic value in various cardiovascular diseases. We investigated the incremental value of LA volume and LAEF as measured by cardiovascular magnetic resonance imaging (CMR) for prediction of appropriate implantable cardioverter defibrillator (ICD) shock or all-cause mortality, in patients with ICD. We conducted a retrospective, multi-centre observational cohort study of patients who underwent CMR prior to primary or secondary prevention ICD implantation. A single, blinded reader measured maximum LA volume index (maxLAVi), minimum LA volume index (minLAVi), and LAEF. The primary outcome was a composite of independently adjudicated appropriate ICD shock or all-cause death. A total of 392 patients were enrolled. During a median follow-up time of 61 months, 140 (35.7%) experienced an appropriate ICD shock or died. Higher maxLAVi and minLAVi, and lower LAEF were associated with greater risk of appropriate ICD shock or death in univariate analysis. However, in multivariable analysis, LAEF (HR 0.92 per 10% higher, 95% CI 0.81-1.04, p = 0.17) and maxLAVi (HR 1.02 per 10 ml/m2 higher, 95% CI 0.93-1.12, p = 0.72) were not independent predictors of the primary outcome. In conclusion, LA volume and function measured by CMR were univariate but not independent predictors of appropriate ICD shocks or mortality. These findings do not support the routine assessment of LA volume and function to refine risk stratification to guide ICD implant. Larger studies with longer follow-up are required to further delineate the clinical implications of LA size and function.

Association between diabetes and haematological malignancies: a population-based study.

AIMS/HYPOTHESIS: Contemporary data for the association of diabetes with haematological malignancies are lacking. We evaluated the risk of developing haematological malignancies and subsequent mortality in individuals with diabetes compared with those without diabetes. METHODS: We conducted a population-based observational study using healthcare databases from Ontario, Canada. All Ontario residents 30 years of age or older free of cancer and diabetes between 1 January 1996 and 31 December 2015 were eligible for inclusion. Using Cox regression analyses, we explored the association between diabetes and the risk and mortality of haematological malignancies (leukaemia, lymphoma, multiple myeloma). The impact of timing on associations was evaluated with analyses stratified by time since diabetes diagnosis (<3 months, 3 months to 1 year, ≥1 year). RESULTS: We identified 1,003,276 individuals with diabetes and age and sex matched these to 2,006,552 individuals without diabetes. Compared with individuals without diabetes, those with diabetes had a modest but significantly higher risk of a haematological malignancy (adjusted HR 1.10 [95% CI 1.08, 1.12] p < 0.0001). This association persisted across all time periods since diabetes diagnosis. Among those with haematological malignancies, diabetes was associated with a higher all-cause mortality (HR 1.36 [95% CI 1.31, 1.41] p < 0.0001) compared with no diabetes, as well as cause-specific mortality. CONCLUSIONS/INTERPRETATION: Diabetes is associated with a higher risk of haematological malignancies and is an independent risk factor of all-cause and cause-specific mortality. Greater efforts for lifestyle modification may not only reduce diabetes burden and its complications but may also potentially lower risk of malignancy and mortality. Graphical abstract.