Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients (NCT03610724), a na phase 2 study. The primary outcome is Overall Response Rate (ORR) as Determined by Local Investigator.

2. Clinical Question

3. Trial Design

This was a Phase II, multicenter, single-arm, open-label trial of tisagenlecleucel in pediatric subjects with relapsed or refractory mature B-cell non-Hodgkin lymphoma. The registry record lists Novartis Pharmaceuticals as sponsor, an enrollment of 34, a start date of 2019-02-15, primary completion on 2021-07-27, and status as completed. The study title also describes the intended safety and efficacy assessment in pediatric patients.

Single-arm means the trial observed participants receiving the study treatment without a concurrent control group. Allocation is listed as not applicable, and masking as none. Consequently, treatment outcomes are not compared within the trial against outcomes in a randomized or otherwise assigned control arm. The design can describe response and safety outcomes in the study population, but by itself cannot separate treatment effects from other explanations for observed outcomes.

The intervention listing includes tisagenlecleucel, lymphodepleting chemotherapy and bridging therapy. The arm description says participants were infused once with CAR-positive viable T cells. The primary endpoint was assessed at 6 months post-infusion. Further details about treatment schedules, eligibility criteria, site procedures, follow-up schedules and protocol deviations are not reported in the registry record.

The primary efficacy population was the Efficacy Analysis Set: participants with aggressive relapsed or refractory B-cell NHL who received an infusion and had measurable disease at baseline. Participants with complete or unknown response after bridging therapy were excluded from that analysis set. This distinction matters because enrollment does not necessarily describe the number included in every endpoint analysis. The registry record does not report the number included in the primary endpoint analysis.

Secondary outcomes listed include duration of response, event-free survival, relapse-free survival, progression-free survival, overall survival, and cellular kinetics parameters. The record lists 15 outcome measures, but it contains no analysis records. The particular estimates, analysis populations, methods and follow-up results for the secondary outcomes 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: Consent, Screening, Pre-treatment, Treatment and Follow-up. In the Pretreatment phase, the subject may have undergone optional bridging therapy or lymphodepleting chemotherapy. Full Analysis Set: 33 Efficacy Analysis Set (EAS): 28; 4 patients with Complete Response prior to infusion \& 1 without a scan prior to infusion excluded from EAS.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Efficacy Analysis Set (EAS): all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline, i.e participants with complete or unknown response after bridging therapy were excluded from the efficacy analysis set.

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: FAS and safety set: all subjects who received an infusion of tisagenlecleucel

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate (ORR) as Determined by Local Investigator, measured over 6 months post-tisagenlecleucel infusion.

The primary endpoint was overall response rate, defined as the percentage of participants whose best overall disease response was complete response or partial response. The assessment was made by the local investigator over the period from tisagenlecleucel infusion until progressive disease or the start of new anticancer therapy, whichever came first. The stated assessment timeframe was 6 months post-infusion.

As a binary endpoint, each participant in the efficacy population contributes to whether the response definition was met. Overall response rate compresses the response assessment into a proportion of participants classified as having complete or partial response. It does not describe how long a response lasted, whether disease later progressed, or survival. Those are distinct outcomes, and the registry separately lists duration of response, progression-free survival and overall survival among secondary outcomes.

In general, response rate is useful for describing the frequency of a defined response within a specified population and assessment period. It also makes the response definition and denominator important: results depend on which participants are included and how response is assessed. Here, the analysis population excludes participants with complete or unknown response after bridging therapy and requires measurable baseline disease and infusion. The endpoint estimate and its 95% confidence interval are not reported in the registry record, so the observed response frequency and its precision cannot be described.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study is recorded as a Phase II single-group trial with no masking. In general, a single-group design estimates outcomes among participants who receive the intervention, rather than comparing outcomes between randomized groups. It can describe what happened in the enrolled and analyzed participants. Without a concurrent comparator, however, it does not provide a direct within-trial estimate of how outcomes differ under another treatment or under no study treatment.

What does the primary endpoint estimate?

Overall response rate is a binary-proportion endpoint: a participant either meets the defined response criterion or does not. The registry defines response as complete response or partial response, based on the best overall disease response from infusion until progressive disease or the start of new anticancer therapy, whichever came first. The local investigator determined the endpoint, and the timeframe was 6 months post-infusion.

For a proportion, the point estimate describes the observed share of the analyzed population meeting the definition. A confidence interval describes uncertainty around that estimate under the statistical method used. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. The record specifies a 95% confidence interval for the endpoint, but reports neither the interval nor the response estimate. Its precision therefore cannot be evaluated from the registry record.

Why is the analysis population important?

The efficacy population is not defined as every enrolled participant. It includes participants with aggressive relapsed or refractory B-cell NHL who received an infusion and had measurable disease at baseline. Participants with complete or unknown response after bridging therapy were excluded. In general, an endpoint estimate applies to the population actually analyzed, so its denominator and eligibility rules determine how broadly the result can be interpreted. The number in this efficacy set and the number analyzed for the primary endpoint are not reported in the registry record.

The study lists an enrollment of 34, while the safety listing identifies 33 participants at risk in the post-infusion group. These counts refer to different record elements and should not be substituted for one another as an efficacy denominator. The registry record does not report a participant flow accounting for the primary efficacy analysis.

What can a single-arm analysis establish?

In general, a single-arm trial can report an observed outcome frequency in the treated population. It cannot, on its own, identify the counterfactual outcome those same participants would have experienced under a different intervention. Differences from historical outcomes would also be vulnerable to differences in participant selection, disease status, assessment, follow-up and other conditions. The registry record does not describe a historical-control analysis, and no such comparison should be inferred.

The trial is open label, with masking listed as none. In general, knowledge of treatment assignment can affect some aspects of care, reporting or assessment, depending on the endpoint and study procedures. The registry defines the primary response as determined by local investigator, but does not report further assessment safeguards or a blinded review process. Such details are not reported in the registry record.

How should planning calculations be understood?

General sample-size illustrations can show how a hypothetical comparison's required enrollment changes under specified assumptions. The registry record's planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect set as a stated fraction of an observed effect. These are planning assumptions, not a description of the trial's single-arm allocation. They do not turn the study into a two-arm comparison, nor do they represent observed power.

For time-to-event planning illustrations, the stated calculation concerns a total number of events; for other outcomes, it concerns participants per arm for 80% or 90% power when those scenarios are shown. In general, such quantities are prospective planning illustrations conditional on assumptions, not results observed in participants. The registry record does not report the trial's own sample-size justification, and it does not report the numerical observed effect needed to assess any effect-based illustration. The planning assumptions should not be mistaken for the original study design or a confirmed target.

What is the role of the secondary outcomes?

The listed secondary outcomes cover response duration, several time-to-event outcomes, survival and cellular kinetics. In general, time-to-event outcomes account for when an event occurs, while the response-rate endpoint records whether a response definition was met. Their interpretation depends on event definitions, censoring rules, follow-up and analysis methods. Those detailed methods and numerical results are not reported in the registry record. The number of listed outcome measures is 15, while the record lists 0 analyses; no specific secondary analysis can therefore be described from the registry entry.

Over-dispersion is a general statistical concern when variability in data exceeds what a simple model assumes. It can make standard errors and confidence intervals too optimistic if the model does not accommodate the extra variability. For this trial's primary binary response endpoint, the registry record does not report a model-based analysis or a dispersion assessment, so no claim about over-dispersion or an adjustment for it can be made.

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("Tisagenlecleucel")
n      <- c(28)
events <- c(9)
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  Tisagenlecleucel  28  9  32.1  15.9  52.4  17.9  50.7  17.9  50.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures, including the primary overall response rate and secondary measures of response duration, event-free survival, relapse-free survival, progression-free survival, overall survival and cellular kinetics. Testing or estimating multiple outcomes can raise multiplicity concerns. In general, when several hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that issue. The registry record does not report whether multiplicity adjustments were planned or used, which outcomes were formally tested, or how any testing hierarchy was defined.

The record lists 0 analyses. It therefore does not provide analysis-specific methods or results for the primary or secondary endpoints. Whether formal hypothesis testing was intended, and whether any interim analyses were planned or conducted, is not reported in the registry record. No statistical analysis plan or sample-size justification is reported in the registry record.

Missing-data handling is also not described. The record does not report rules for participants with unavailable response assessments, incomplete follow-up, withdrawal, or other missing endpoint information. The endpoint definition excludes participants with complete or unknown response after bridging therapy from the efficacy analysis set, but that exclusion rule is not a general missing-data procedure and should not be treated as one. The number excluded for this reason and the number with missing primary endpoint data are not reported in the registry record.

The primary efficacy population is defined by disease status, infusion and baseline measurability, with the stated exclusion after bridging therapy. The registry does not report the final analysis denominator or a participant disposition for the primary endpoint. As a result, the effects of eligibility, exclusions and missing assessments on the response estimate cannot be evaluated from 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: cytokine release syndrome (24.2%), pyrexia (21.2%), pleural effusion (9.1%), febrile neutropenia (6.1%), abdominal pain (6.1%).

The post-infusion safety group lists 33 participants at risk for serious adverse events, of whom 24 were affected. For other adverse events, 33 were at risk and 33 were affected. The record separately lists 17 deaths in the post-infusion group and 1 death in the pre-infusion group. These are counts recorded for the safety groupings; they are not, by themselves, estimates of treatment-attributable risk.

The serious adverse event terms listed with percentages are cytokine release syndrome, 24.2%; pyrexia, 21.2%; pleural effusion, 9.1%; febrile neutropenia, 6.1%; abdominal pain, 6.1%; and depressed level of consciousness, 6.1%. These percentages should be read as the registry's reported values for the listed terms. The record does not provide further detail about event timing, severity grades, duration, recurrence, or attribution for each term.

Safety summaries require attention to the group and denominator being described. The post-infusion and pre-infusion death groups are distinct entries, and the pre-infusion group lists no participants at risk for the adverse event categories. Death counts alone do not establish cause. The registry record does not report whether deaths were considered related to treatment or provide additional explanations, so causal conclusions are not supported by these summaries.

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

The record establishes that a Phase II, multicenter, open-label, single-arm study evaluated tisagenlecleucel in pediatric, adolescent and young adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma. It defines a primary efficacy endpoint based on investigator-determined complete or partial response at 6 months post-infusion and identifies a specific efficacy analysis population. It also records selected safety counts and serious adverse event terms.

It does not report the primary response rate or its 95% confidence interval. Accordingly, the registry record does not reveal how many participants in the efficacy analysis set met the response definition, how precise the estimate was, or how it compares with any alternative. The enrollment count is not a substitute for the endpoint denominator, and the listed safety figures cannot be used to reconstruct efficacy.

Even if a response estimate were available, the design would remain single arm. In general, an outcome frequency in a single treated group is descriptive and does not establish the outcome difference that would have occurred under a concurrent alternative. The registry record reports no randomized comparison. It also does not provide the numerical results or detailed analyses for the secondary outcomes, including response duration or survival.

The safety entries show that serious and other adverse events were recorded among participants in the post-infusion group, and that deaths were listed in both post-infusion and pre-infusion groupings. These entries do not establish that the intervention caused any particular event or death. The registry record does not report further attribution details or circumstances needed to interpret those outcomes causally.

The appropriate statistical reading is therefore limited but clear: the record describes the design, definitions, analysis population rules and selected safety information, while leaving the primary efficacy result and its uncertainty unreported. Neither efficacy nor comparative benefit can be concluded from the information recorded.

14. Why This Trial Matters Statistically

This trial raises several important statistical interpretation issues. First, the endpoint is a proportion, but its meaning depends on a defined population and response rule. The primary analysis set requires infusion and measurable baseline disease, and it excludes participants with complete or unknown response after bridging therapy. The registry's enrollment of 34 is therefore not automatically the denominator for the efficacy estimate. The final analysis count is not reported in the registry record.

Second, the endpoint is a local-investigator assessment in an open-label study. In general, endpoint assessment procedures and knowledge of treatment can matter when interpreting a response classification. The registry record defines the response categories and assessment window, but does not report further safeguards or a blinded review procedure.

Third, the single-arm design makes the estimand descriptive rather than a direct comparative effect. The record can identify the population and outcome the study intended to assess, but without a concurrent comparator it cannot establish a within-trial difference against another intervention. This distinction remains important even when the endpoint is clinically meaningful.

Finally, precision and completeness matter. A 95% confidence interval is specified, yet neither it nor the response estimate appears in the registry record. Secondary outcomes are listed, but numerical results and analysis details are not. Safety figures are present, but do not establish causality. These gaps make it especially important to distinguish what the registry defines from what it actually reports as a result.

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 statistical interpretation is that the registry record does not report the primary endpoint result. It gives the overall response rate definition and 95% confidence interval type, but not the response estimate, interval limits or analysis denominator. Thus, the efficacy outcome's magnitude and precision are unavailable from this record.

The trial has no concurrent comparator and is open label. These design features limit the interpretation to outcomes observed within the study group and do not support a randomized comparison. The registry record does not report a comparative analysis against another group.

The efficacy population is restricted to participants who received infusion and had measurable disease at baseline, with participants having complete or unknown response after bridging therapy excluded. The number of participants meeting each rule and the final primary analysis count are not reported in the registry record. The handling of missing response assessments is also not reported.

Although secondary outcomes are listed, their results, detailed definitions, analysis methods and follow-up summaries are not reported in the registry record. The entry does not report a statistical analysis plan, multiplicity approach, interim analysis information or the trial's own sample-size justification. The safety listing provides selected event terms and group counts but not further event-level context, attribution, severity grading or circumstances of deaths. These limitations constrain conclusions to the recorded design and descriptive safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients — NCT03610724.
• Registry record last updated 2024-06-20; status last verified 2024-06.
• Results first posted 2024-03-19.
• 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

NCT03610724 is recorded as a completed Phase II, multicenter, single-arm, open-label study sponsored by Novartis Pharmaceuticals. It enrolled 34 participants and evaluated tisagenlecleucel in pediatric, adolescent and young adult patients with relapsed or refractory B-cell non-Hodgkin lymphoma. Participants were infused once with CAR-positive viable T cells; lymphodepleting chemotherapy and bridging therapy are also listed.

The primary endpoint was local-investigator-determined overall response rate at 6 months post-infusion, defined as complete or partial response. Its efficacy population required infusion and measurable baseline disease and excluded participants with complete or unknown response after bridging therapy. The primary estimate, confidence interval and analysis denominator are not reported in the registry record.

Secondary outcomes include response duration, time-to-event outcomes, survival and cellular kinetics. Selected safety counts and serious adverse event terms are recorded, but further attribution and event context are not reported in the registry record.