Aim: Compare thrombotic risk in people with congenital hemophilia A (PwcHA) to the general non-hemophilia A (HA) population. Patients & methods: US claims databases were analyzed to identify PwcHA. Incidence rates of myocardial infarction, pulmonary embolism, ischemic stroke, deep vein thrombosis and device-related thrombosis were compared with a matched cohort without HA. Results: Over 3490 PwcHA were identified and 16,380 individuals matched. PwcHA had a similar incidence of myocardial infarction and pulmonary embolism compared with the non-HA population, but a slightly higher incidence of ischemic stroke and deep vein thrombosis. The incidence of device-related thrombosis was significantly higher in PwcHA. Conclusion: This analysis suggests that PwcHA are not protected against thrombosis, and provides context to evaluate thrombotic risk of HA treatments.

Background Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the USA to treat adult patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL) based on ZUMA-3 study results. We report updated ZUMA-3 outcomes with longer follow-up and an extended data set along with contextualization of outcomes to historical standard of care. Methods Adults with R/R B-ALL received a single infusion of KTE-X19 (1 × 106 CAR T cells/kg). Long-term post hoc subgroup assessments of ZUMA-3 were conducted. Outcomes from matched patients between historical clinical trials and ZUMA-3 patients were assessed in the retrospective historical control study SCHOLAR-3. Results After 26.8-months median follow-up, the overall complete remission (CR) rate (CR + CR with incomplete hematological recovery) among treated patients (N = 55) in phase 2 was 71% (56% CR rate); medians for duration of remission and overall survival (OS) were 14.6 and 25.4 months, respectively. Most patients responded to KTE-X19 regardless of age or baseline bone marrow blast percentage, but less so in patients with > 75% blasts. No new safety signals were observed. Similar outcomes were observed in a pooled analysis of phase 1 and 2 patients (N = 78). In SCHOLAR-3, the median OS for treated patients from ZUMA-3 (N = 49) and matched historical controls (N = 40) was 25.4 and 5.5 months, respectively. Conclusions These data, representing the longest follow-up of CAR T-cell therapy in a multicenter study of adult R/R B-ALL, suggest that KTE-X19 provides a clinically meaningful survival benefit with manageable toxicity in this population. Trial Registration: NCT02614066.

Background: The ZUMA-3 trial of KTE-X19 in relapsed/refractory (r/r) adult B-cell precursor acute lymphoblastic leukaemia (B-ALL) utilizes a single arm design. To contextualize these results, a synthetic control (SC) study derived from individual patient-level data (IPD) sampled from historical clinical trials (CTs) was constructed. Aims: To compare the overall survival (OS) and objective complete response rate at week 24 (OCR24) results of the ZUMA-3 pivitol study using a matched (SC) derived from IPD from CTs. Methods: This study had two distinct phases: firstly, CTs from which patients were sampled were identified using the medidata enterprise data store (MEDS). The second phase of this study constructed SCs to the ZUMA-3 population, one SC for patients naïve to blinatumomab (blin) or inotuzuamab (ino) therapy (SCA-1) and one in blin or ino pre-treated patients (SCA-2). All analysis were pre-specified and conducted by an external third party to Kite Pharma. For the trial identification phase, the MEDS database was searched to identify CTs that had inclusion and exlusion criteria congruent with ZUMA-3 and treatment assignments representative of current standards of care inclusive of blin, ino or chemotherapy regimens. Once appropriate CTs had been identified the endpoints were re-engineerd to match the same defintions as the ZUMA-3 trial. For the SC construction phase, propensity score (PS) matching was used. The PS was derived as a function of the number of previous lines of therapy, prior allo-SCT, age, sex, ECOG, Philadelphia chromosome status, percentage bone marrow blasts and extramedullary disease. For outcomes analysis, time-to-event endpoints of interest were analyzed using the Kaplan-Meier method and compared using a Cox proportional hazard regression model. OCR rate was described through crude incidence rates and corresponding 95% CI. ln addition, an odds ratio together with associated 95% CI and 2-sided p-value were estimated from a logistic regression model. Results A total of 20 SCA-1 patients were matched to 20 patients from ZUMA-3 and a total 20 SCA-2 patients were matched to 29 patients from ZUMA-3. Analysis of the SCA-1 cohort shows an OCR24 of 85% (95% CI 62.1%, 96.8%) in the Zuma-3 patients and 35.0% (95% CI 15.4, 59.2) among propensity matched controls. This corresponds to an OR of 10.5 (95% CI 2.3, 48.7; p-value 0.0031). No OCR24 data was available for SCA-2. A post hoc analysis was conducted in order to further contextualize the OCR24 rate. ZUMA-3 patients irrespective if they had been pre-treated with blin or ino were matched to patients from HCTs who were previously naïve to blin or ino therapy (SCA-3). The OCR24 rate in the ZUMA-3 arm was 69.8% (95% CI 55.7%, 81.7%) while for SCA-3 patients was 35.8% (95% CI 23.1%, 50.2%) meaning that ZUMA-3 patients had 4.1 times higher odds of achieving OCR in comparison to SCA-3 patients (95% CI 1.8, 9.3) p-value 0.0009. The comparison of overall survival (OS) between all matched ZUMA-3 and all SCA patients demonstrated a significantly higher median OS of 18.20 months (95% CI 12.22, NE months) for patients in ZUMA-3 versus 5.49 months (95% CI 3.32, 9.23 months) in SCA-3. A cox regression model showed that ZUMA-3 patients had a 64% lower risk of death with a hazard ratio 0.36 (95% CI 0.20, 0.66) p-value 0.0005. Conclusion: This comparative study demonstrated a clinically relevant improvement of OCR24 and OS following KTE-X19 vs available therapies and provides strong evidence for its use in adult patients with R/R B-ALL Disclosures Shah: Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Precision Biosciences: Consultancy; Adaptive Biotechnologies: Consultancy. Faghmous: Kite A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Whitmore: Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh: GSK: Current equity holder in publicly-traded company; Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company; Immatics: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Xu: Gilead Sciences: Other: stock or other ownership ; Kite, A Gilead Company: Current Employment.

Background When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set “time zero,” the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. Methods A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. Results Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. Conclusions Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. Highlights There are multiple methods available from which an analyst may select “time zero” in an external control cohort. This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts. Careful thought and clear justification should be used when selecting the strategy for a study.