Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults (NCT02535806), a na phase 2 study. The primary outcome is Number of Subject With Adverse Events.

2. Clinical Question

The clinical question is therefore about the experience of participants treated with the combination regimen, rather than a comparison of that regimen with another treatment. For the primary outcome, the registry describes toxicities graded according to CTCAE v 4.0. The recorded adverse-event results indicate that one participant was affected by a serious adverse event. The registry lists respiratory failure among the serious adverse-event terms, with a reported value of 50.0%; the denominator for that percentage is not specified in the registry record.

The trial description states that bone marrow evaluation after blood-count recovery was intended to assess complete remission, defined in the description as less than 5% bone marrow blasts, and minimal residual disease status. Those are planned clinical assessments, not reported results. Further treatment, with or without HSCT, was described as being at the discretion of the primary physician. The registry record does not report the results of these subsequent assessments or treatment decisions.

3. Trial Design

This is a phase II, single-group study sponsored by Children's Mercy Hospital Kansas City. Its official title describes a pilot study of mitoxantrone-based four-drug reinduction in combination with bortezomib for relapsed or refractory ALL or LL in children and young adults. The registry record lists enrollment of 2 and the status as terminated. The recorded start is 2015-07 and primary completion is 2017-05-25. The reason for termination is not reported in the registry record.

The study has no separate control arm: allocation is listed as not applicable, the model is single group, and masking is none. As a result, its recorded outcomes describe participants in the treatment arm; they do not provide a randomized estimate of a treatment difference. A comparison with historical experience or another treatment group is not reported in the registry record.

The treatment description includes bortezomib (Velcade) by IV push on days 1, 4, 8, and 11 at 1.3 mg/m2/dose. Intrathecal methotrexate is described for CNS-negative patients on days 1 and 8, while intrathecal methotrexate, hydrocortisone, and cytarabine are described for CNS-positive patients on days 1, 8, 15, and 22. Other listed drugs include dexamethasone, mitoxantrone, vincristine, and pegaspargase. The registry record does not provide a complete regimen schedule for every listed drug in the treatment-arm description.

The brief description says the study was designed to investigate the combination in high-risk ALL relapse and relapsed LL. The record does not report a sample-size justification, a statistical analysis plan, interim analyses, or the reason for the small recorded enrollment. These omissions limit assessment of how the study was intended to address its clinical questions and why recruitment ended.

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subject With Adverse Events, measured over 36 days.

The primary endpoint counts participants with adverse events during a 36-day timeframe. The registry describes toxicities as assessed and graded according to CTCAE v 4.0. A participant count is a binary outcome at the participant level: each person is classified according to whether the specified event occurred during the stated observation period. This differs from counting every event, because a participant could potentially experience more than one event while still contributing once to a participant-based count.

Safety endpoints are used to characterize harms observed during treatment and the defined follow-up period. Their interpretation depends on how events were defined, assessed, graded, and attributed, as well as on the completeness of observation. The registry record identifies the grading framework and timeframe, but does not report detailed event definitions, attribution procedures, monitoring completeness, or a fuller safety analysis plan.

The posted primary results report one participant affected by a serious adverse event and zero participants affected in the registry's other adverse-event count. The record also reports zero deaths. These are descriptive counts from a very small single-group study. They do not estimate a comparative safety effect, and the registry record does not provide enough information to infer that unrecorded events did not occur. Remission, minimal residual disease, and overall survival are named as secondary outcomes, but their results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is a count of participants with adverse events, not a count of all adverse-event episodes. In a participant-level binary outcome, each person is classified as having or not having the event of interest within the stated timeframe. The registry reports a 36-day timeframe and identifies CTCAE v 4.0 as the toxicity grading framework. It does not provide additional detail about how repeated events, event attribution, or incomplete observation were handled.

In general, participant counts are easy to read but do not convey the full distribution of event severity, timing, duration, or recurrence. A count of participants with an event can be useful for a concise safety description, but it is not a substitute for event-level detail. The registry record gives a serious-event count and a separate other-event count, without reporting a fuller event listing or a detailed severity distribution.

Why does the single-group design matter?

A single-group study describes outcomes among participants who received the study regimen. It has no concurrent control group from which to estimate what would have happened under a different treatment. General statistical interpretation therefore distinguishes an observed outcome from a treatment effect: a treatment effect requires a comparison that supports a contrast between treatment conditions. The registry record lists allocation as not applicable, masking as none, and the model as single group, so the posted results are not a randomized comparison.

Without a comparator, differences from other studies or usual care would require assumptions about comparability that are not established in this record. Such comparisons may be affected by differences in participant characteristics, eligibility, treatment, outcome assessment, and follow-up. No adjusted or historical comparison is reported in the registry record.

How should precision be understood?

General: a confidence interval describes a range of values compatible with the observed data under a specified statistical model. It communicates uncertainty as well as the point estimate. Small studies generally yield limited precision, particularly for infrequent outcomes. The registry record does not report confidence intervals for the adverse-event counts, so the results should be read as counts rather than precise estimates of underlying event rates.

Over-dispersion is a general concern when count data vary more than a simple statistical model expects. It matters when the analysis models counts and relies on a particular variance assumption. The primary endpoint is defined as participants with an event, and the registry record does not report a count-model analysis or a variance model. There is therefore no basis in the registry record for saying that an over-dispersion adjustment was used or was required.

What do the planning assumptions mean?

The registry record describes sample-size illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. It says time-to-event illustrations use the total number of events, while other illustrations use participants per arm. These are planning assumptions, not a description of this study's single-group design. They do not establish that the study had a two-arm design, and they are not observed power. Numerical planning results and a trial-specific sample-size justification are not reported in the registry record.

General: power is a design-stage probability under specified assumptions, while observed power calculated after results are known does not resolve uncertainty in the observed estimate. A planning illustration can show how a hypothetical future study might be sized under its assumptions; it cannot change the information available from this study's recorded enrollment. The registry record does not report the assumptions needed to assess whether a particular planning scenario is appropriate for these outcomes.

What analyses are documented?

The record lists 4 outcome measures and 0 analysis records. The absence of analysis records means that results of those analyses are not documented in the registry record; it does not establish that no analyses were performed. The record does not report inferential tests, model specifications, adjustment factors, confidence intervals, or a prespecified hierarchy of outcomes. No recalculated treatment comparison is appropriate for a single-group study without a comparator.

Because remission, minimal residual disease, and overall survival results are not reported, their statistical precision and analysis methods cannot be evaluated. The registry record does not state how the planned bone marrow assessment was analyzed, how survival time was defined, or how participants without an observed outcome were handled. Those omissions prevent a fuller appraisal of the statistical evidence beyond the posted descriptive safety counts.

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("Treatment Arm")
n      <- c(2)
events <- c(1)
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  Treatment Arm  2  1  50.0  1.3  98.7  9.5  90.5  9.4  90.6

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary adverse-event outcome and secondary outcomes for remission rate, post-induction minimal residual disease, and 2-year overall survival. Considering several outcomes can raise multiplicity concerns: when multiple statistical tests are conducted, the chance of at least one apparently notable result may increase. General methods for addressing this include prespecifying a primary outcome, defining a testing hierarchy, or adjusting inference across tests. The registry record does not report a multiplicity strategy, and the secondary outcome results are not reported.

The registry lists 0 analysis records. This means the registry record does not document analysis results or methods for the listed outcomes; it does not prove that analyses were not conducted. The analysis populations are not reported in the registry record. In particular, it does not specify whether all enrolled participants were included in each outcome analysis or how eligibility deviations, treatment exposure, or incomplete follow-up were handled.

Missing-data methods are also not reported. The record does not state whether outcome data were complete, how missing assessments were treated, or whether any sensitivity analyses were planned or performed. For a study with a small recorded enrollment, even missing information about a single participant could materially affect descriptive interpretation. That is a general point about small studies, not evidence that any particular outcome was missing in this trial.

The registry describes intended bone marrow assessment after blood-count recovery, but does not report how participants who did not reach that assessment were handled. The follow-up and censoring rules for overall survival are not reported in the registry record. Consequently, the completeness and analysis of the planned secondary outcomes cannot be assessed.

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 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: respiratory failure (50.0%).

The safety results record 1 participant affected by a serious adverse event, 0 participants affected in the other adverse-event count, and 0 deaths. The serious-event results list respiratory failure with a reported value of 50.0%. The registry record does not state the denominator for that term-level percentage, so its basis cannot be confirmed from the record alone.

The serious-event count and the term-level percentage are different kinds of summaries. The count identifies affected participants in the treatment arm; the term listing gives a percentage for a reported serious-event term. The record does not provide enough detail to determine whether the term percentage is based on participants, events, or another denominator. It is therefore preferable not to translate that percentage into a participant count.

These figures describe the registry entries, not a comparison with another treatment. They do not establish causality, the full range of event severity, or the risk in a broader patient population. The record identifies CTCAE v 4.0 and a 36-day timeframe for the primary outcome, but does not report detailed event-level data or the completeness of safety follow-up.

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

The posted results offer a limited description of adverse events recorded in a single-group phase II study with enrollment of 2. They document 1 participant affected by a serious adverse event, 0 in the other adverse-event count, and 0 deaths. Respiratory failure is listed as a serious-event term with a reported value of 50.0%, but the term-level denominator is not reported in the registry record.

These observations do not show how the regimen compares with another treatment, because the study has no comparator arm. They also do not establish that the regimen caused or prevented the recorded events. The small enrollment means that the experience described cannot provide a precise estimate of event frequency for a larger group. No confidence intervals or comparative analyses are reported in the registry record.

The study description identifies remission, minimal residual disease, and overall survival as secondary outcomes, but does not report their results. The intended bone marrow evaluation and the stated definition of complete remission describe planned assessment, not an observed remission result. The registry's terminated status does not explain why the study stopped or what happened to the planned outcome assessments.

Accordingly, the results can be read as a record of a small number of safety observations, not as evidence of comparative benefit or harm. They do not support a conclusion about remission, minimal residual disease, or survival. The registry record also does not report a statistical analysis plan, missing-data methods, or analysis populations that would permit a more complete evaluation of the study's statistical evidence.

14. Why This Trial Matters Statistically

This study is statistically notable because its clinical aim and the information recorded at completion are quite different in scope. The trial description concerns a combination reinduction regimen and identifies remission, minimal residual disease, and overall survival as secondary outcomes. The posted results described in the registry record are limited to participant-level adverse-event counts, while the secondary outcome results are not reported.

The single-group design makes the distinction between describing outcomes and estimating a treatment effect especially important. A count of events among treated participants can document what was recorded in the study, but it cannot by itself quantify how outcomes would differ under another treatment. The lack of a comparator is therefore a design limitation for causal or comparative questions, not merely a matter of choosing a different statistical test.

The small recorded enrollment also illustrates how little precision can be expected from a very limited study population. A single participant's outcome has a substantial influence on a description based on so few observations. General statistical principles caution against treating a sparse event count as a stable estimate for a broader population.

Finally, the registry record demonstrates why outcome plans and outcome results must be distinguished. Naming remission, minimal residual disease, and survival as outcomes does not provide their observed values. The record's termination status and absence of analysis records leave important questions about assessment and reporting unresolved. These limitations make careful description more appropriate than broad conclusions.

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 limitations are specific to the information recorded for this trial. The registry lists enrollment of 2, and the study is single group with no comparator. Consequently, the adverse-event counts provide little information about event frequency in a broader population and cannot support a between-treatment contrast. The record does not report a confidence interval or other uncertainty measure for the posted safety results.

The study is marked terminated, but the reason for termination is not reported in the registry record. The record does not explain whether termination affected recruitment, follow-up, outcome assessment, or analysis. It also does not report whether participants completed the intended regimen or the completeness of safety monitoring.

The primary outcome is described as a participant count over 36 days, with toxicities graded according to CTCAE v 4.0. Additional details about event definitions, attribution, severity results, repeat events, and follow-up completeness are not reported in the registry record. The serious-event term respiratory failure is listed with a percentage, but its denominator is not specified.

Although the record identifies remission rate, post-induction minimal residual disease, and 2-year overall survival as secondary outcomes, their results and analysis methods are not reported. The record also does not report analysis populations, missing-data handling, multiplicity methods, or a statistical analysis plan. These gaps prevent evaluation of the planned clinical outcomes and limit interpretation of the safety counts to a narrow descriptive account.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Four Drug Reinduction With Bortezomib for Relapsed or Refractory ALL or LL in Children and Young Adults — NCT02535806.
• Registry record last updated 2019-08-13; status last verified 2019-07.
• Results first posted 2019-08-13.
• 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

NCT02535806 is a phase II, single-group study sponsored by Children's Mercy Hospital Kansas City. It investigated a mitoxantrone-based four-drug reinduction regimen combined with bortezomib for children and young adults with relapsed or refractory ALL or LL. The registry record lists enrollment of 2, no masking, and terminated status. The recorded start is 2015-07, with primary completion on 2017-05-25.

The primary outcome counts participants with adverse events over 36 days; toxicities were assessed and graded according to CTCAE v 4.0. The registry reports 1 participant with a serious adverse event, 0 in the other adverse-event count, and 0 deaths. Respiratory failure is listed among serious-event terms with a value of 50.0%, but its denominator is not reported in the registry record.

Remission rate, post-induction minimal residual disease, and 2-year overall survival are named as secondary outcomes, but their results are not reported. A reason for termination, analysis methods, and missing-data handling are also not reported in the registry record.