We tested the feasibility of setting individualized glycemic goals and factors influencing targets set in a clinical trial in elderly patients with type 2 diabetes.A 24-week, randomized, double-blind, placebo-controlled study was conducted in 45 outpatient centers in seven European countries. 278 drug-naïve or inadequately controlled (mean HbA1c 7.9%) patients with type 2 diabetes aged ≥70 years with HbA1c levels ≥7.0% and ≤10.0% were enrolled. Investigator-defined individualized HbA1c targets and the impact of baseline characteristics on individualized treatment targets was evaluated.The average individualized HbA1c target was set at 7.0%. HbA1c at baseline predicted a target setting such that higher the HbA1c, more aggressive was the target (P<0.001). Men were more likely to be set aggressive targets than women (P=0.026). Frailty status of patients showed a trend towards significance (P=0.068), whereas diabetes duration, age, or polypharmacy did not. There was heterogeneity between countries regarding how baseline factors were viewed.Despite training and guidance to individualize HbA1c goals, targets were still set in line with conventional values. A strong influence of country-specific guidelines on target setting was observed; confirming the importance of further education to implement new international guidelines in older adults.
In the absence of head-to-head trials, an indirect-treatment comparison can estimate the treatment effect of tisagenlecleucel in comparison with blinatumomab on rates of complete remission (CR) and overall survival (OS) in patients with relapsed or primary refractory (R/R) acute lymphoblastic leukemia (ALL). Patient-level data from two pivotal trials, ELIANA (tisagenlecleucel; n = 79) and MT103-205 (blinatumomab; n = 70), were used in comparisons of CR and OS, controlling for cross-trial difference in available patient characteristics. Five different adjustment approaches were implemented: stabilized inverse probability of treatment weight (sIPTW); trimmed sIPTW; stratification by propensity score quintiles; adjustment for prognostic factors; and adjustment for both prognostic factors and propensity score. Comparative analyses indicate that treatment with tisagenlecleucel was associated with a statistically significant higher likelihood of achieving CR and lower hazard of death than treatment with blinatumomab. The tisagenlecleucel group exhibited a higher likelihood of CR than the blinatumomab group in every analysis regardless of adjustment approach (odds ratios: 6.71-9.76). Tisagenlecleucel was also associated with a lower hazard of death than blinatumomab in every analysis, ranging from 68% to 74% lower hazard of death than with blinatumomab, determined using multiple adjustment approaches (hazard ratios: 0.26-0.32). These findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with R/R ALL.
Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (<18y and ≥18y) [Rives et al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age (<18y and ≥18y). Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged <18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest - including cytokine release syndrome (CRS) and neurotoxicity - were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged <18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged <18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the <18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy. Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.
7535 Background: Chimeric antigen receptor T-cell therapies tisa-cel and liso-cel are effective treatments for r/r DLBCL (Schuster 2019, Abramson 2020). This study compared efficacy outcomes of tisa-cel and liso-cel in r/r DLBCL using matching-adjusted indirect comparison (MAIC). Methods: Individual patient-level data (IPD) from JULIET (tisa-cel; NCT02445248; 02/2020 datacut) were weighted to match the patient population in TRANSCEND (liso-cel; NCT02631044; 08/2019 datacut). Baseline prognostic factors available in both trials were adjusted for age, sex, histology, ECOG performance status [ECOG PS], left ventricular ejection fraction, radiologic sum of product diameters, lactate dehydrogenase, prior stem cell transplantation [SCT], use of bridging therapy, and number of and refractoriness to prior therapies, in the MAIC. Overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and overall response (OR) rate were compared. Primary analyses compared infused patients in JULIET (N=106, excluding 8 without lymphodepleting chemotherapy [LDC] and 1 large cell neuroendocrine carcinoma) with efficacy-evaluable set in TRANSCEND (N=256, infused patients). A scenario analysis compared JULIET infused to TRANSCEND primary analysis set (PAS) (N=133, dose level 2, excluding those with ECOG PS 2, prior allogeneic SCT, primary mediastinal B-cell lymphoma, follicular lymphoma [FL] 3B, or transformation from indolent lymphoma besides FL). Sensitivity analyses included JULIET patients with only fludarabine-based LDC or only adjusted significantly different baseline prognostic factors. Safety outcomes were not compared because adverse event management has evolved and differed between the two trials; MAIC is unable to adjust for such differences. Results: After adjusting for differences in baseline characteristics, OS, PFS, and CR were comparable between tisa-cel infused patients and the liso-cel efficacy-evaluable set (Table). The results were consistent across all scenario and sensitivity analyses. OR rate trended higher in the TRANSCEND efficacy-evaluable set (72.7% vs. 62.9%, p=0.07) and was higher in TRANSCEND PAS than in the respectively matched JULIET infused set (74.4% vs. 60.9%, p < 0.05). Conclusions: The MAIC results indicate there is no evidence suggesting differences in OS, PFS and CR between tisa-cel and liso-cel in r/r DLBCL. Analyses using IPD from both trials and/or real-world evidence are warranted to confirm these findings.[Table: see text]
Introduction: CD19 CAR T cells induce complete remissions in ≥40%of heavily pretreated patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL). However, a significant proportion of patients progress early after therapy. Thus, to prospectively identify patients most suitable for currently available commercial CAR T-cell products, we assessed the predictive value of clinical and laboratory parameters for PFS in r/r DLBCL patients treated with Axicabtagene Ciloleucel or Tisagenlecleucel at our institution. Methods: Patient, disease, and treatment characteristics of r/r DLBCL patients treated with CD19-CAR T cells were retrospectively assessed. Pre-defined patient and lymphoma characteristics known to confer adverse outcomes in DLBCL were evaluated for their association with PFS by univariable log-rank tests, as well as multivariable stepwise Cox regression analyses. Characteristics encompassed age, refractoriness to first-line therapy, no. of prior therapy lines, tumor volume, presence of bulky disease, presence of extranodal disease (END), Ann Arbor stage, IPI, LDH, and ECOG, all assessed at time of lymphodepletion. Results: As of November 2020, 35 patients have been transfused. Median age was 60 years (range 19-82). ECOG was 0-1 in 23, and 2-3 in twelve patients at CAR T-cell transfusion. Only 3 of the 35 transfused patients (9%) would have met the inclusion criteria of the pivotal clinical trials at all eligibility assessment timepoints (enrolment, apheresis, and time of lymphodepletion). CRS occurred in 32/35 patients (80% CRS°1-2, 11%°3). 16 patients (46%) experienced ICANS (29%°1-2, 14%°3-4, and 3%°5).Response assessment after three months was available for 34/35 patients. Objective response rate was 53%, with complete remission in 15 (44%) and partial remission in three patients (9%).In univariable analyses, apart from primary refractory disease (p = 0.79), all pre-selected characteristics were suggestive to be associated with shorter PFS (p = 0.002-0.061). We therefore included these variables (p < 0.1) in multivariable Cox regression analyses. In the resulting model, presence of END was associated with inferior PFS (Hazard ratio [HR] 11.3, p = 0.02), adjusted for prior therapy lines (HR 1.3, p = 0.06) and ECOG > 1 (HR 2.3, p = 0.12). Other variables did not improve the prognostic validity of the model. Conclusions:We provide real-world evidence that CD19-CAR T cells induce remissions in a substantial proportion of r/r DLBCL patients, despite very frequent non-eligibility for pivotal clinical trials in our patient cohort. Extranodal disease at transfusion was associated with significantly shorter PFS both in uni-and multivariable analyses. To address END-associated resistance mechanisms, we have set up a comprehensive translational research program with specific focus on the nodal vs. extranodal lymphoma microenvironment.
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