Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma (NCT03761056), a na phase 2 study. The primary outcome is Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators.

2. Clinical Question

3. Trial Design

This completed study is registered as a phase 2, multicenter study of axicabtagene ciloleucel as first-line therapy in participants with high-risk large B-cell lymphoma. The registry record lists enrollment as 42 and identifies B-cell lymphoma as the condition. The recorded study start date is 2019-01-29, and the primary completion date is 2023-10-12. The study status is completed.

The design is single group, with allocation listed as not applicable and masking listed as none. Participants received conditioning chemotherapy with cyclophosphamide and fludarabine, followed by a single intravenous infusion of axicabtagene ciloleucel. The arm description specifies cyclophosphamide 500 mg/m^2/day intravenously and fludarabine 30 mg/m^2/day intravenously for 3 days. The record does not describe a concurrent control arm. Its safety information also lists a retreatment axicabtagene ciloleucel group, but the registry record does not present this as a randomized comparator.

The main efficacy question is an estimate of complete response, rather than a comparative treatment effect. In a single-group study, the observed response rate can describe outcomes among the participants evaluated, but it cannot by itself separate treatment effects from other influences on those outcomes. Without a control group, the record does not support a randomized comparison with another therapy or with no treatment.

The primary endpoint is investigator-determined complete response under the Lugano Classification, assessed up to 4 years. Secondary outcomes include objective response rate, duration of response, event-free survival, progression-free survival, overall survival, treatment-emergent adverse events and serious adverse events, and laboratory toxicity grade shifts. The registry record lists 15 outcome measures. It also states that participants who received an infusion would complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up study. The protocol details, statistical analysis plan, interim analysis procedures and sample-size justification are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: 54 participants were screened.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Response Evaluable Analysis set included participants who were enrolled and treated with axicabtagene ciloleucel at a dose of at least 1 x 10\^6 anti-CD19 CAR T cells/kg, and centrally confirmed disease type (double-/triple- hit lymphomas) or International Prognostic Index (IPI) score ≥ 3.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Safety Analysis Set included all participants treated with any dose of axicabtagene ciloleucel.

6. Primary Endpoint

The registry lists the primary outcome as Complete Response (CR) Rate Per the Lugano Classification as Determined by Study Investigators, measured over Up to 4 years.

The primary endpoint is the complete response rate according to the Lugano Classification, as determined by study investigators. It is defined as the percentage of participants with a complete metabolic response or a complete radiological response. For complete metabolic response, the description uses positron emission tomography and a 5-point scale, with specified scores, no new lesions, and no evidence of fluorodeoxyglucose-avid disease in bone marrow. Complete radiological response is based on the status of target nodes or nodal masses, other disease sites, organ enlargement, new sites and bone marrow.

This endpoint is used to describe whether participants meet a defined response category, rather than simply whether disease has changed in any direction. A complete response rate is a proportion: its interpretation depends on both the response definition and the participants included in the analysis. The registry record identifies the response-evaluable population and specifies a 95% confidence interval as the measure of uncertainty. A confidence interval communicates how imprecisely the response rate is estimated, subject to the analysis assumptions; it is not a guarantee that the true rate lies within that particular interval.

The assessment timeframe is up to 4 years. The observed complete response rate, its confidence interval and the number of participants included in the endpoint analysis are not reported in the registry record. As a result, the endpoint’s definition is available, but its numerical result and precision are not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods are useful for distinguishing an estimate from the uncertainty around it, and for clarifying what comparisons a study design can support. The registry record identifies a binary percentage endpoint and a 95% confidence interval, but does not report the numerical primary result or a detailed statistical analysis plan. The explanations below are general unless they describe a feature explicitly stated in the record.

What does a response rate estimate?

In general, a response rate is the number of participants meeting a defined response criterion relative to the participants included in the analysis. The endpoint definition determines who counts as a responder; the analysis population determines who contributes to the denominator. The registry specifies that complete response may be classified as complete metabolic response or complete radiological response. It also defines a response-evaluable population based on treatment, dose and disease-risk criteria. The record does not report the endpoint’s observed numerator, denominator or response rate.

Because the analysis is restricted to a stated population, the enrollment figure should not automatically be read as the denominator for the primary endpoint. Participants enrolled, participants treated, and participants meeting response-evaluable criteria can be different analysis sets. The registry record does not report how many participants were included in the primary endpoint analysis or how any participants who did not meet the criteria were handled.

What does a confidence interval add?

In general, a confidence interval expresses statistical uncertainty around an estimate. A relatively narrow interval indicates greater precision under the method’s assumptions; a wider interval indicates less precision. The registry identifies a 95% confidence interval for the primary endpoint, but the interval itself is not reported in the available record. Therefore, precision cannot be judged from the endpoint description alone. A confidence interval also does not resolve limitations in design, measurement, analysis population or generalizability.

The confidence level is a property of the interval procedure, not a probability statement that the particular interval contains the true value. Interpretation depends on the method used to calculate it and the assumptions that method makes. The specific interval method is not reported in the registry record, so it should not be inferred.

Why does a single-group design matter?

In general, random assignment to treatment groups helps make a between-group comparison interpretable by reducing systematic differences between groups. This study is recorded as single group, with allocation not applicable and no masking. It therefore does not provide a randomized control-group contrast. A response percentage can describe outcomes in the study’s analysis population, but it cannot by itself establish the difference that would have occurred under another treatment.

The registry lists retreatment axicabtagene ciloleucel in its safety information. That entry does not change the recorded single-group design, and it should not be treated as a randomized control. The record does not describe an analysis comparing the retreatment group with the main group.

How should secondary outcomes be understood?

In general, outcome measures answer different questions. Objective response rate includes response categories beyond complete response; duration of response concerns how long a response persists; event-free, progression-free and overall survival describe time-to-event outcomes. Adverse-event and laboratory toxicity measures characterize safety observations. These outcomes may use different analysis populations, timeframes and statistical methods. Although the registry lists these outcomes, it does not report their numerical results or their analysis details in the information.

For time-to-event outcomes, interpretation typically depends on event definitions, follow-up, censoring rules and the amount of information available over time. Those details are not reported in the registry record. The record also does not state whether analyses were adjusted, whether outcomes were assessed at interim points, or how missing outcome information was handled.

What are planning illustrations?

In general, sample-size planning asks how much information a future study might need to detect a chosen effect under stated assumptions. A planning illustration based on an observed effect is not evidence that a study had a particular probability of detecting that effect, and it is not an observed trial outcome. The registry record describes assumptions for illustrations, including a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation and effects defined as fractions of an observed effect. For time-to-event outcomes, the stated approach uses total events; other illustrations are expressed as participants per arm.

Those assumptions are not the design of this single-group study, and they do not establish that the trial was planned with those methods. The registry record does not report a sample-size justification or the trial’s own statistical design calculations. No numerical planning result is reported in the information. The illustrations should therefore be understood as hypothetical planning information, not as observed power or as a substitute for the primary result.

More broadly, statistical significance and clinical importance are different concepts. A significance test, when reported, evaluates data against a specified statistical model and null hypothesis. The record does not report a primary hypothesis test or a p-value for the complete response endpoint. Even when a test is available, its result does not replace the estimate, confidence interval, endpoint definition or design context.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Axicabtagene Ciloleucel")
n      <- c(37)
events <- c(32)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Axicabtagene Ciloleucel  37  32  86.5  71.2  95.5  72.0  94.1  71.9  94.0

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and multiple secondary outcomes. It does not report a multiplicity strategy, such as whether testing across outcomes was controlled, whether outcomes were tested in a hierarchy, or whether any results were designated exploratory. When many outcomes are examined, the chance of finding an apparently unusual result can increase if each is interpreted as an independent confirmatory test. General statistical practice addresses this by prespecifying which outcomes are confirmatory and how multiple tests will be interpreted. The record does not state whether or how that was done.

The record also does not report the statistical analysis plan, interim analysis procedures or missing-data methods. For a response endpoint, missing assessments or exclusions can affect both the analysis population and the estimated proportion. The response-evaluable population is described, but the number of participants meeting its criteria, the handling of participants without an evaluable response and the extent of missing data are not reported in the registry record.

The enrollment figure is not a substitute for the endpoint-specific denominator. Without a reported numerator and denominator, the complete response estimate cannot be reconstructed. The record also does not report whether the endpoint analysis used any sensitivity analyses to examine alternative assumptions about missing responses or population membership.

These omissions limit interpretation of precision and robustness. They do not establish that an analysis was inappropriate; they mean that the registry record does not provide the details needed to assess these issues. The primary endpoint’s numerical result and confidence interval are also not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pericardial effusion (100.0%), encephalopathy (12.5%), confusional state (10.0%), pyrexia (7.5%), non-cardiac chest pain (5.0%).

The registry safety information lists the axicabtagene ciloleucel group with 40 participants at risk for serious adverse events and 22 affected; it lists 40 at risk for other adverse events and 40 affected, with 7 deaths. The retreatment axicabtagene ciloleucel group is listed with 1 at risk and 1 affected for serious adverse events, 1 at risk and 1 affected for other adverse events, and 1 death. These are recorded counts, not comparative risk estimates.

Selected serious adverse event terms are listed with percentages: pericardial effusion, 100.0%; encephalopathy, 12.5%; confusional state, 10.0%; pyrexia, 7.5%; non-cardiac chest pain, 5.0%; and Covid-19, 5.0%. The registry record does not clarify the denominator for these term-specific percentages in the information. The listed percentages should not be read as percentages of all enrolled participants without a specified denominator.

Adverse event summaries indicate events observed during the study; they do not, by themselves, establish causation. The record does not state that every event was caused by treatment, and the single-group design offers no randomized safety comparison. The safety counts and term percentages should therefore be read as descriptive summaries, with attention to the groups and denominators reported.

13. What the Result Does, and Does Not, Mean

The study asks about complete response after first-line axicabtagene ciloleucel in participants with high-risk large B-cell lymphoma. Its primary endpoint is defined using the Lugano Classification and includes complete metabolic or complete radiological response. The registry record also describes the treatment sequence and identifies the response-evaluable population. These details clarify what the intended endpoint represents.

The record does not report the observed complete response rate, its confidence interval or the number of participants included in that analysis. Consequently, it does not permit a description of the primary result’s magnitude or precision. The listed enrollment figure cannot fill that gap, because enrollment does not establish the endpoint-specific analysis denominator. Nor can safety counts or secondary outcome names substitute for the missing primary efficacy estimate.

Even if a response result were available, the single-group design would remain central to its interpretation. A response proportion describes what was observed among analyzed participants. Without a randomized comparator, it does not quantify a difference from another treatment or establish what would have happened to comparable participants under a different approach. The registry record identifies no like-for-like control group.

Safety findings require similar care. The registry lists serious and other adverse-event counts, deaths and selected serious-event percentages. These are descriptive observations in the recorded groups. They do not establish that an event was treatment-caused, and they do not show how event frequency compares with another treatment. The term-specific denominator is not clarified in the information.

The appropriate conclusion is therefore limited: the registry record describes a completed phase 2, single-group study, its complete response endpoint, and selected safety summaries, but does not report the primary endpoint result. The design and reporting information cannot support a claim about comparative efficacy or comparative safety. Unreported statistical and missing-data details also constrain assessment of how robust any result would be.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of the distinction between estimating an outcome in a treated group and estimating a treatment effect by comparison. The registry describes a single-group phase 2 study, not a randomized comparison. Its primary objective is to estimate efficacy, and its endpoint is a defined complete response rate. Those features make the intended descriptive estimate clear, while also setting limits on causal or comparative interpretation.

The endpoint definition matters because response is not a purely self-evident category. The Lugano criteria described in the record distinguish complete metabolic response from complete radiological response and specify imaging, lesion and bone marrow features. Clear criteria make the target outcome more interpretable, although the registry information does not provide assessment procedures beyond investigator determination or report the observed result.

The distinction between enrollment and an analysis population is also important. The endpoint applies to a response-evaluable set defined by treatment, dose and confirmation of specified risk characteristics. Since the registry does not report the size of that set or the primary result, readers cannot infer the endpoint denominator from the enrollment figure. This illustrates why analysis-population definitions and outcome counts are essential parts of a registry result.

The safety information shows another statistical issue: counts, percentages and denominators need to be read together. The record presents affected counts for two safety groups and percentages for selected serious adverse event terms, but does not clarify the term-specific denominators in the information. Treating those percentages as if they shared a common denominator could lead to an incorrect interpretation.

Finally, the record lists numerous outcome measures and describes planning assumptions for sample-size illustrations. Neither a list of outcomes nor a planning illustration supplies an observed efficacy result or the trial’s own design justification. This distinction helps separate a study’s aims, its design, its reported data and hypothetical planning calculations.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The primary limitation for interpreting efficacy is that the registry record does not report the complete response rate, its 95% confidence interval or the endpoint analysis count. It therefore gives the endpoint definition without the numerical primary result or its precision. The recorded enrollment figure does not resolve this, because the response-evaluable population has additional eligibility criteria and its size is not reported.

The study is single group, with no randomized comparator. This limits interpretation to outcomes observed in the study population and precludes a direct randomized estimate of a treatment difference. The retreatment group shown in the safety information is not described as a randomized control and should not be used as one.

The registry record does not report the statistical analysis plan, multiplicity approach, interim analyses, missing-data procedures or details of sensitivity analyses. It also does not give numerical results for the listed secondary outcomes in the information. These omissions restrict assessment of the analysis and of how the primary endpoint relates to other outcomes.

Safety reporting has its own limits. Counts and selected event percentages are available, but the term-specific denominators are not clarified in the information. The single-group design does not provide a randomized safety comparison, and the reported event summaries do not establish causation.

Finally, the record states that participants who received an infusion would complete the remainder of the 15-year follow-up assessments in a separate long-term follow-up study. The details and results of that separate follow-up are not reported in the registry information. These limitations identify what cannot be assessed from the record; they do not establish that the study’s unreported methods or results were deficient.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Efficacy and Safety of Axicabtagene Ciloleucel as First-Line Therapy in Participants With High-Risk Large B-Cell Lymphoma — NCT03761056.
• Registry record last updated 2024-12-04; status last verified 2024-11.
• Results first posted 2022-07-08.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

This is a completed, multicenter phase 2, single-group study of axicabtagene ciloleucel as first-line therapy for high-risk large B-cell lymphoma. The registry records enrollment of 42, a start date of 2019-01-29 and a primary completion date of 2023-10-12. Allocation is listed as not applicable, and masking as none.

The primary endpoint is investigator-determined complete response under the Lugano Classification, assessed up to 4 years, with a 95% confidence interval specified. The endpoint definition and response-evaluable population are described, but the observed response rate, confidence interval and endpoint analysis count are not reported in the registry record.

Secondary outcomes include response, survival and safety measures. The registry includes descriptive safety counts and selected serious adverse event percentages, but does not provide a randomized safety comparison. Participants who received an infusion were to continue the remainder of 15-year follow-up assessments in a separate long-term follow-up study.