Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma (NCT01700946), a non-randomized phase 2 study. The primary outcome is 3-year Overall Survival Rate of Patients With Relapsed ALL.

2. Clinical Question

The study asks about 3-year overall survival among participants with first relapse or primary refractory precursor B-cell acute lymphoblastic leukemia (ALL) treated with risk-directed therapy. Its primary outcome description focuses on participants with relapsed ALL, while the stated objective and treatment description also include B-lymphoblastic lymphoma. The registry record does not report a numerical survival estimate or a confidence interval for this outcome, so the magnitude and precision of the posted primary result cannot be assessed from the record.

Treatment depended on risk group. Standard-risk participants received chemotherapy, while high-risk participants were intended to receive chemotherapy followed by hematopoietic stem cell transplantation. The treatment description includes an induction regimen with chemotherapy, rituximab and infusion of haploidentical natural killer cells. This was not a randomized comparison of the two risk groups: risk status determined the treatment pathway, and the groups therefore do not serve as like-for-like controls for one another.

The primary clinical question is consequently about survival after the study’s risk-directed treatment strategy, rather than whether one treatment pathway is superior to the other. The registry lists additional outcomes concerning positive minimal residual disease and CD20 expression, but their numerical results are not reported in the registry record. The record also does not explain whether the primary outcome was assessed in a specific analysis population or how participants with incomplete follow-up were handled.

3. Trial Design

This was a phase II, non-randomized, parallel-group study sponsored by St. Jude Children's Research Hospital. The registry lists planned enrollment of 80 and marks the study as completed. The recorded start date is 2013-04-15, and the primary completion date is 2021-07-24. No masking was used. The registry record does not report the rationale for the planned enrollment or details of a sample-size justification.

The two groups were Standard Risk and High Risk. As described in the registry, standard-risk participants received chemotherapy, while high-risk participants received chemotherapy followed by hematopoietic stem cell transplantation. Transplant was conditional on a suitable donor being found and minimal residual disease being negative. These are risk-directed pathways, not randomized alternatives. Differences in outcomes between the groups could reflect their underlying risk categories and other differences between participants, as well as treatment; a direct causal comparison is not supported by the design.

The described treatment began with three blocks of induction chemotherapy. The first block included chemotherapy, rituximab and haploidentical natural killer cell infusion. Standard-risk participants were to continue chemotherapy for an approximately 2-year total treatment duration. The high-risk pathway included consideration of transplantation. The registry’s intervention listings include agents such as dexamethasone, vincristine, clofarabine, cyclophosphamide, etoposide, aldesleukin and pegaspargase, alongside other agents listed in the arm descriptions.

The record lists five outcome measures and three analyses. It does not give enough detail to establish the analysis populations, the statistical model used for the primary outcome, or whether the reported outcomes were prespecified in the same form as the current 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.

Overall Study

Reasons for not completing this period:

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: All participants enrolled on study.

6. Primary Endpoint

The registry lists the primary outcome as 3-year Overall Survival Rate of Patients With Relapsed ALL, measured over 3 years of follow-up since the on-study date.

The primary endpoint is the 3-year overall survival rate of patients with relapsed ALL, described as an estimate among participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy. The timeframe is 3 years of follow-up since the on-study date. Overall survival concerns whether participants are alive over the specified follow-up period; it is not a measure of remission, disease response, quality of life or treatment toxicity.

A fixed-time survival rate provides a clinically interpretable summary of survival through a stated follow-up horizon. It can incorporate follow-up information from participants who have different observation durations, provided the analysis accounts appropriately for participants whose vital status is no longer observed. In general, a confidence interval conveys the uncertainty around an estimated survival rate: a wider interval indicates less precision, while a narrower interval indicates greater precision. The registry specifies a 95% confidence interval as the measure of dispersion for this outcome.

The numerical survival estimate and its 95% confidence interval are not reported in the registry record. The statistical method used to estimate survival, the number of participants included in that analysis, and the handling of incomplete follow-up are also not reported in the registry record. Therefore, the endpoint’s definition is available, but its observed value and precision cannot be interpreted from the registry entry.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Overall survival is a time-to-event outcome: the event of interest is death, and the analysis concerns survival over follow-up. A survival rate at a chosen time point expresses the estimated proportion surviving through that horizon. Because participants may have different lengths of observation, time-to-event analyses commonly account for participants who are alive at their last known follow-up without treating them as if they had died. This is a general explanation; the particular estimator, censoring rules and follow-up procedures used in this study are not reported in the registry record.

What does the confidence interval tell readers?

A confidence interval communicates uncertainty around an estimate. The registry specifies a 95% confidence interval for the primary survival outcome. In general, it describes a range of values compatible with the data and the method used, under the assumptions of that method. It is not a guarantee that the true value lies within the interval, and it does not correct for weaknesses in design, incomplete follow-up or bias. Since the numerical interval is not reported in the registry record, its width and the precision of the survival estimate cannot be evaluated.

Why does the non-randomized design matter?

Random assignment can help balance prognostic characteristics between treatment groups, on average. Here, treatment was risk-directed: standard-risk participants received a chemotherapy pathway, and high-risk participants had a pathway that included chemotherapy followed by transplantation. Risk group was not randomly assigned. A difference in outcomes between the groups could therefore arise from baseline risk, treatment, transplant eligibility, donor availability or other differences. This is a general limitation of interpreting non-randomized group comparisons, not evidence that any particular factor explains an outcome in this study. The registry explicitly identifies the arms as not being a like-for-like control comparison.

How should event counts be read?

For a binary outcome, an event count records how many participants experienced the event among those assessed or at risk, according to the registry’s definitions. Counts can be useful descriptions, but without a prespecified comparison and suitable adjustment they do not establish that one treatment caused more or fewer events. The registry’s safety data give counts for serious events, other events and deaths in the listed groups. Definitions, event windows, attribution to treatment and methods for handling repeated events are not reported in the registry record. The serious-event term listed at 5.6% is aspartate aminotransferase increased; the record does not supply additional context for interpreting that percentage.

What do planning calculations represent?

General sample-size planning estimates depend on assumptions about the effect to detect, the significance level, allocation, outcome distribution and analysis method. The planning illustrations associated with the posted analysis are described as using a two-sided significance level of 0.05, equal allocation, a normal approximation and effects expressed as fractions of the observed effect. They are illustrations based on an observed effect, not the original trial design justification. For time-to-event outcomes, the stated planning approach concerns a total number of events; other outcomes are expressed as participants per arm. These calculated planning quantities are not observed power, do not change the number actually enrolled, and do not establish that the study was adequately powered. The registry record does not report its own sample-size assumptions or justification.

Which statistical details remain unclear?

The registry lists three analyses, but does not describe the methods for those analyses in enough detail to determine the survival estimator, confidence-interval construction, treatment of missing observations, adjustment for covariates, or whether the analyses were exploratory or confirmatory. The record also does not describe any interim analyses or stopping rules. Those details matter because different analytic choices can affect estimates and uncertainty, especially when follow-up is incomplete or groups differ at baseline. Their absence from the registry entry is not proof that the study team did not use such procedures; they are simply not reported in the registry record.

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("STANDARD RISK", "HIGH RISK")
n      <- c(18, 24)
events <- c(17, 13)
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  STANDARD RISK  18  17  94.4  72.7  99.9  74.2  99.0  74.0  98.7
ARM  HIGH RISK  24  13  54.2  32.8  74.4  35.1  72.1  34.9  72.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists five outcome measures and three analyses. It does not report how the analyses were mapped to the outcomes, whether all listed outcomes were analyzed, or whether any outcome was designated as secondary or exploratory beyond the labels given in the registry. A multiplicity plan covering multiple endpoints or analyses is not reported in the registry record. When several outcomes or statistical tests are examined, the chance of at least one apparently notable result can increase; statistical plans may address this in different ways. Without the plan, it is not possible to determine whether or how multiplicity was considered.

The registry record does not report the number of participants included in the primary survival analysis, the analysis population definition, or how missing outcome information was handled. It does not state the extent of loss to follow-up or how participants with unknown vital status were treated. For secondary outcomes, the record does not provide the number assessed or a missing-data approach. These omissions limit interpretation of both the estimates and their potential representativeness.

The safety information includes denominators for the listed groups, but the reason those safety denominators differ from the planned enrollment is not reported in the registry record. The record also does not describe whether all participants contributed to every outcome or whether exclusions occurred. Consequently, the stated enrollment and outcome-specific counts should not be assumed to refer to an identical analysis population.

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: aspartate aminotransferase increased (5.6%).

The registry reports serious adverse event counts for three groups. In Standard Risk, 18 participants were at risk and 1 was affected; in High Risk, 24 were at risk and 0 were affected. For All Patients Enrolled on the Study, 42 were at risk and 1 was affected. The registry separately lists other-event counts: 18 at risk and 18 affected in Standard Risk, 24 at risk and 23 affected in High Risk, and 42 at risk and 41 affected across all patients. Death counts are 3, 10 and 13, respectively.

These entries are descriptive counts. The registry record does not specify whether a death was related to treatment, the timing of the events, the number of events per participant, or how event severity and duration were assessed. The group counts should not be interpreted as a randomized comparison, because risk category determined the treatment pathway. The reason the safety denominator of 42 is smaller than planned enrollment of 80 is not reported in the registry record. Aspartate aminotransferase increased is listed among the top serious adverse event terms at 5.6%; context needed to interpret this term and percentage is not further reported in the registry record.

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

The study addresses a difficult clinical setting through a risk-directed treatment strategy for pediatric participants with relapsed or refractory precursor B-cell ALL or lymphoblastic lymphoma. Its design includes distinct treatment pathways for standard-risk and high-risk participants, including chemotherapy and, for eligible high-risk participants, hematopoietic stem cell transplantation. The registry identifies 3-year overall survival as the primary outcome and specifies a 95% confidence interval.

However, the registry record does not report the numerical primary survival estimate or confidence interval. It therefore does not support a judgment about the observed 3-year survival level or its precision. Numerical findings for the listed secondary outcomes are also not reported in the registry record. The safety counts provide limited descriptive information but do not establish causation or allow a fair treatment comparison.

The non-randomized, risk-directed design is important to interpretation. Standard-risk and high-risk participants are not interchangeable groups, and their treatment pathways differ. Comparing their outcomes cannot isolate the effect of a particular treatment from the risk characteristics that led to the pathway. The record also does not provide the analysis methods and population details needed to evaluate possible selection, missing-data or follow-up effects.

Accordingly, the registry entry establishes what the study set out to evaluate and describes its design and some safety counts. It does not, by itself, provide enough numerical outcome information to establish the size or precision of the primary result, or enough design information to support a causal comparison between pathways.

14. Why This Trial Matters Statistically

This trial illustrates why the design and endpoint need to be read together. Overall survival at 3 years is a meaningful time-to-event summary, but an endpoint definition alone is not a result. The registry record names the outcome and its confidence-interval measure while not reporting the numerical estimate or interval. Readers therefore cannot assess the observed survival level or how precisely it was estimated from this record.

The risk-directed structure is also statistically consequential. Participants were not randomly assigned to the Standard Risk and High Risk pathways. These groups were defined by risk, and treatment differed accordingly, including transplantation in the high-risk pathway for participants meeting the stated conditions. The groups cannot be treated as exchangeable controls. A raw contrast between them would not isolate the effect of the treatment pathway.

Finally, the registry’s safety counts demonstrate the distinction between describing events and attributing them to treatment. Counts by group can communicate what was recorded, but the available information does not establish causation, provide complete event context or resolve differences between the groups. The listed planning illustrations are also distinct from evidence about the study’s original design: they are calculations based on an observed effect, not observed power. These points make transparent outcome reporting, analysis methods and population definitions essential for understanding what a clinical trial can and cannot establish.

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.

Several trial-specific limitations follow from the registry record. The numerical 3-year overall survival estimate and its 95% confidence interval are not reported in the registry record, and numerical results for the listed secondary outcomes are also absent. This prevents assessment of the primary estimate, its precision and the secondary findings using this record alone.

The study was non-randomized and assigned treatment pathways according to risk. The Standard Risk and High Risk groups are not like-for-like controls, so a comparison between them cannot establish the causal effect of the different pathways. The high-risk pathway also depended on finding a suitable donor and having negative minimal residual disease before proceeding to transplantation. The record does not report how many participants met those conditions or proceeded to transplant.

Planned enrollment was 80, while the safety results list 42 participants in the all-patients group. The reason for this difference is not reported in the registry record. The record does not explain the safety analysis population, provide outcome-specific analysis populations, or describe missing data and follow-up completeness. It also does not report the statistical methods for the primary analysis, multiplicity handling, interim analyses or original sample-size justification. These gaps restrict assessment of precision, bias and the scope of inference; they do not establish that particular procedures were or were not used outside the registry entry.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma — NCT01700946.
• Registry record last updated 2022-09-28; status last verified 2022-09.
• Results first posted 2022-09-28.
• 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

The registry identifies NCT01700946 as a completed phase II, non-randomized, parallel-group study sponsored by St. Jude Children's Research Hospital. Planned enrollment was 80. Standard-risk participants received a chemotherapy pathway, while high-risk participants were assigned a pathway that included chemotherapy and possible hematopoietic stem cell transplantation. The primary outcome was 3-year overall survival among participants with relapsed or primary refractory precursor B-cell ALL, with a 95% confidence interval specified.

The registry record does not report the numerical primary outcome or confidence interval. It lists safety counts for serious events, other events and deaths, as well as secondary outcomes concerning minimal residual disease and CD20 expression. Numerical secondary-outcome results, analysis populations and detailed statistical methods are not reported in the registry record.