Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma (NCT00873093), a non-randomized phase 2 study. The primary outcome is Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy.

2. Clinical Question

This is a response-assessment question within a treatment study, not a randomized estimate of how much bortezomib changes response relative to another treatment. The registry summary states that the pilot studies side effects and how well the combination works. However, the primary endpoint is a complete-remission rate at a specified point in treatment; it does not, by itself, answer questions about later outcomes or establish what would have happened to the same patients under a different regimen.

The intended primary population excludes some of the broader groups described in the trial record, including T-cell ALL, lymphoblastic lymphoma, and patients outside the stated age and relapse-time criteria. The endpoint definition therefore should not be generalized automatically to every group enrolled in the trial. The number of eligible and evaluable participants contributing to this primary endpoint is not reported in the registry record.

3. Trial Design

This is a Phase II pilot trial, listed as completed, with a non-randomized allocation, no masking, and a single-group model. The registry reports enrollment of 148. The recorded start is 2009-03 and the primary completion is 2014-09. The sponsor is the National Cancer Institute (NCI).

The trial concerns bortezomib in combination with intensive re-induction chemotherapy for patients with relapsed ALL or LL. The registry lists several chemotherapy interventions, including L-asparaginase, doxorubicin hydrochloride, therapeutic hydrocortisone, vincristine sulfate, cytarabine, prednisone, and pegaspargase, as well as bortezomib. The arm descriptions divide patients into groups defined by disease type, relapse timing, and age. Those descriptions lay out chemotherapy across Re-Induction Blocks 1, 2, and 3. They do not describe a randomized comparison between treatment options, and they do not provide a dose or detailed schedule for bortezomib.

The listed groups include pre-B ALL relapse groups divided by time from diagnosis and age, a T-cell ALL group, and a T-cell lymphoblastic lymphoma group. These categories help describe the clinical groups treated, but they should not be interpreted as independently randomized arms. The primary endpoint population is more specific than the overall enrollment: it is limited to eligible and evaluable pre-B ALL patients age <= 21 years with relapse < 36 months from diagnosis, identified as strata 1 and 2.

With no randomized control group and no masking, the design can describe outcomes observed during this treatment program but does not isolate the treatment's effect against a concurrent control. The registry record does not report a formal sample-size justification, allocation procedures beyond the non-randomized designation, interim analyses, or a detailed statistical analysis plan. It also does not report the number analyzed for the primary endpoint. The total enrollment should therefore not be treated as the endpoint denominator without an analysis population count.

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:

Analysis population for the primary outcome, as defined in the registry: The analysis on this primary outcome is limited to pre-B ALL with age \<= 21 years who relapsed \< 36 months only (stratum 1 \& 2) per protocol section 9.2.1.

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 Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy, measured over The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy..

The primary endpoint is the percentage of participants who achieved a second complete remission at the end of Block 1 of re-induction chemotherapy. The outcome description defines the measure as the percentage of eligible and evaluable patients who achieved complete response at that time. The stated assessment time is Day 36 of Block 1.

A response rate is a binary-outcome summary: each person is classified according to whether the defined response occurred, and the rate expresses the share meeting that definition. The endpoint gives a focused snapshot of response at a specified treatment milestone. It does not describe the duration of remission, later relapse, survival, or the full course of treatment. Those are distinct outcomes and cannot be inferred from a Block 1 response measure.

The endpoint's analysis population is limited to pre-B ALL, age <= 21 years, with relapse < 36 months from diagnosis. The outcome description also requires patients to be eligible and evaluable. These criteria matter because an endpoint rate depends on who is included in its denominator. The registry record does not report the number eligible and evaluable, the number achieving complete response, or the resulting percentage. It therefore supports an explanation of what was intended to be measured, but not a numerical summary of the observed primary outcome.

The registry also identifies minimal residual disease outcomes at the ends of Blocks 1, 2, and 3. These are secondary outcomes and do not replace the primary complete-remission endpoint. Their observed results are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Clinical trial results are easiest to interpret when the question, endpoint, analysis population, and design are considered together. In this study, the primary outcome is a binary response measure: a patient either meets the stated complete-response definition at the end of Block 1 or does not. The registry expresses this outcome as a percentage of eligible and evaluable participants. The actual percentage and its contributing counts are not reported in the registry record.

What does a response percentage describe?

A response percentage describes the proportion of an analysis group meeting a defined outcome. It is a summary of what happened among those included in that group. Its denominator is essential: a percentage based on all enrolled participants can differ from one based only on eligible and evaluable participants. For this endpoint, the registry identifies eligibility and evaluability criteria but does not state how many participants met them or how many were included in the analysis. The enrollment of 148 should not be substituted for the missing endpoint denominator.

The endpoint is tied to a specific milestone, the end of Block 1, Day 36. It is therefore a time-specific response measure. It does not by itself capture whether a response continued, whether disease later recurred, or whether other outcomes occurred. The registry lists minimal residual disease rates at the ends of Blocks 1, 2, and 3 as secondary outcomes, but their observed values are not reported in the registry record.

Why does the design matter?

Random assignment is a way to make treatment groups comparable, on average, with respect to both measured and unmeasured characteristics. This trial is listed as non-randomized, unmasked, and single-group. It therefore does not provide a randomized control comparison. The several listed clinical groups reflect disease and patient categories; they should not be treated as treatment-versus-control arms. The registry record also warns that these groups are not a like-for-like control comparison.

Without a concurrent randomized control group, observed outcomes can be described, but the difference between the outcome under the study regimen and the outcome that would have occurred under another regimen cannot be identified from this design alone. In general, differences in patient characteristics, disease features, or care can influence observed outcomes. This is a design limitation, not a statement about the direction or size of any effect in this trial.

What would uncertainty measures add?

A confidence interval is a statistical summary of uncertainty around an estimated quantity. In general, it gives a range of values compatible with the observed data under the method used. For a response percentage, the interval depends on the observed number of responses, the analysis denominator, and the interval method. A confidence interval is not a guarantee that the true value lies in the interval, and it does not repair limitations in study design. No confidence interval for the primary response rate is reported in the registry record.

A p-value, in general, summarizes how unusual data would be under a specified null hypothesis and statistical model. It is not the probability that a treatment works, nor does it measure the size or clinical importance of an effect. No primary-outcome p-value or analysis result is reported in the registry record. The registry lists 0 analyses, so it is not possible to identify from this record a tested hypothesis or inferential procedure for the endpoint.

How should sample-size illustrations be understood?

The stated planning illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The illustration is described as using a fraction of the observed effect. In general, planning calculations ask how many participants might be needed under chosen assumptions to detect a specified contrast with a chosen level of power. Those estimates depend on the assumed effect, outcome variability, allocation, and statistical method.

Such a calculation is distinct from a trial's observed power. Observed power is not an informative substitute for an effect estimate and its uncertainty. The planning values are illustrations, not a record of how this trial was designed. In addition, the stated equal-allocation, two-arm assumptions do not describe the trial's listed single-group, non-randomized design. The registry record does not report a trial-specific sample-size justification, and no numerical planning estimates or observed effect are reported in the registry record.

Why does over-dispersion matter in general?

Over-dispersion is a general issue in statistical models for counts or other outcomes when the observed variability is greater than the model assumes. If ignored, model-based standard errors can be too small, making uncertainty appear less than it is. This concept does not establish that over-dispersion occurred in this trial. The registry record does not report a model for the primary binary endpoint, an over-dispersion assessment, or any fitted analysis that would support such a conclusion.

For a binary response endpoint, the essential reporting elements include the outcome definition, analysis population, response count, denominator, estimate, and an uncertainty measure. The registry gives the endpoint definition and target population, but not the observed response count, denominator, estimate, or uncertainty measure. General statistical concepts can explain how those elements would be interpreted, but cannot fill in absent trial results.

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("Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy", "Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy) ")
n      <- c(54, 46)
events <- c(39, 29)
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  Pre-B ALL Relapse 18-36 Mths From Dx (Chemotherapy  54  39  72.2  58.4  83.5  59.1  82.4  59.0  82.4
ARM  Pre-B ALL Relapse <18 Mths From Dx (Chemotherapy)   46  29  63.0  47.5  76.8  48.6  75.5  48.5  75.5

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures and 0 analyses. The primary endpoint is the second complete-remission rate at the end of Block 1. The record also identifies minimal residual disease rates at the ends of Blocks 1, 2, and 3 as secondary outcomes. The observed results for these outcomes are not reported in the registry record.

Multiplicity arises when several outcomes or hypotheses are assessed. In general, the more statistical tests conducted, the more likely it is that at least one result may appear noteworthy by chance if each test is interpreted without accounting for the others. Strategies can include identifying a primary outcome in advance, adjusting inference, or clearly distinguishing confirmatory from exploratory outcomes. The registry record does not report a multiplicity strategy, a hierarchy among the outcomes, or an analysis plan specifying how multiple outcomes were to be handled.

Missing-data methods matter because participants with unavailable or unevaluable outcome information may differ from those with observed results. The primary outcome is defined for eligible and evaluable patients, but the number excluded, reasons for missing or unevaluable assessments, and any missing-data method are not reported in the registry record. It is therefore not possible to assess how missing endpoint information was handled or how that handling might affect a response estimate.

The primary analysis population is described as pre-B ALL, age <= 21 years, relapse < 36 months from diagnosis, strata 1 and 2, with eligible and evaluable patients. The record does not report the analyzed count for this population, how protocol deviations were treated, or whether a different population was used for any analysis. No intention-to-treat or per-protocol analysis population is stated in the registry record. Overall enrollment of 148 does not resolve these missing details.

12. Safety Results

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

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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death nos (50.0%), blood bilirubin increased (25.0%), peripheral sensory neuropathy (25.0%), sepsis (16.3%), pancreatitis (13.6%).

The registry reports serious and other adverse-event figures separately for five clinical groups. For each group, it gives the number at risk and the number affected for serious events and for other events. These are descriptive counts. They should be read within their respective groups, not as a randomized comparison of treatment strategies.

For example, the registry lists 61 at risk and 47 affected for serious events in the pre-B ALL relapse 18-36 months group age <= 21 years. For other events, that group has 61 at risk and 58 affected. The pre-B ALL relapse <18 months group age <= 21 years has 49 at risk and 40 affected for serious events, and 49 at risk and 44 affected for other events. These are counts, not estimates adjusted for differences in follow-up or patient characteristics. The registry record does not provide enough detail to interpret them as comparative risks.

Selected serious-event terms are listed with percentages, including Death NOS at 50.0%, blood bilirubin increased at 25.0%, and peripheral sensory neuropathy at 25.0%. The denominator and calculation details for these term percentages are not reported in the registry record. The group-level death fields are not populated with death counts, so the Death NOS term should not be interpreted as a complete accounting of deaths in the trial.

Safety counts depend on how events were defined, collected, and followed. The registry record does not report all such details in the information summarized for these figures. These numbers describe reported events and do not establish that the treatment caused them or support a comparison with an unassigned alternative.

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

The registry record establishes the trial's broad purpose and planned outcome: a Phase II pilot of bortezomib with combination re-induction chemotherapy in young patients with relapsed ALL or LL, with a primary complete-remission assessment at the end of Block 1. It also defines a narrower primary population and lists secondary minimal residual disease outcomes. Those details clarify the question the study set out to address.

The record does not report the observed primary response percentage, its numerator or denominator, or an uncertainty interval. It also lists 0 analyses. The available registry information therefore does not permit a statistical judgment about the magnitude or precision of the primary response result. A conclusion about whether a treatment works or does not work cannot be drawn from the endpoint definition, overall enrollment, or adverse-event counts alone.

Even if an outcome estimate were available, a single-group, non-randomized design would not provide the same causal comparison as a randomized trial. The observed response would describe participants in the study, not the difference between their outcomes under the study treatment and their outcomes under a control treatment. The groups defined by disease type, age, and relapse timing do not create that missing randomized contrast.

The safety figures are useful as descriptive reports of events in the listed groups. They do not by themselves establish causation, comparative safety, or the overall balance of benefits and harms. The percentages attached to selected serious-event terms lack a stated denominator in the registry information, and the group-level death counts are not reported.

In general, interpreting a clinical trial requires alignment between the question, the endpoint, the population analyzed, the design, and the uncertainty around estimates. Here, the question and endpoint are described, but the principal outcome result and analysis details are not. The appropriate reading is consequently bounded: the registry documents a completed pilot study and its intended assessments, while key efficacy and analysis results are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable because it illustrates the difference between an endpoint definition and an endpoint result. The registry identifies a specific complete-remission measure, assessment time, and target population. Those details are important for deciding what a result would mean. Yet the observed percentage and the number of patients contributing to it are not reported in the registry record. Without those quantities, readers cannot assess either the outcome level or its precision.

The record also shows why overall enrollment should not automatically be treated as the denominator for a restricted endpoint. Enrollment is 148, while the primary outcome applies only to eligible and evaluable pre-B ALL patients age <= 21 years whose relapse occurred < 36 months from diagnosis. The number meeting those conditions is not reported. A clear analysis population is central to interpreting any percentage, particularly when trial enrollment spans several clinical groups.

Design is equally important. The study is non-randomized and single-group, and the registry warns that the groups do not form a like-for-like control comparison. This means that descriptive outcomes should not be mistaken for a randomized treatment effect. The distinction applies even when a trial has a clearly defined endpoint or a substantial overall enrollment.

Finally, the record provides an opportunity to distinguish planned sample-size illustrations from trial design information. The stated illustration assumptions describe a hypothetical two-arm, equal-allocation calculation using a normal approximation. They do not establish that the trial used that design, justify its enrollment, or demonstrate observed power. The trial-specific sample-size justification and statistical analysis plan are not reported in the registry record.

These features matter because good statistical interpretation depends not only on numerical results, but also on knowing who was analyzed, how the comparison was formed, and what uncertainty remains. In this record, the design and outcome definitions can be described, while the primary numerical result and key analysis details remain unavailable.

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 primary endpoint result. It gives no response count, analysis denominator, percentage, confidence interval, or p-value. The registry lists 0 analyses. The outcome definition therefore cannot be converted into an assessment of the observed response or its precision.

The stated primary population is restricted to eligible and evaluable pre-B ALL patients age <= 21 years with relapse < 36 months from diagnosis. The overall enrollment of 148 includes a broader trial population, but the count satisfying the primary analysis criteria is not reported in the registry record. Reasons for exclusion or unevaluable assessments are also not reported.

The single-group, non-randomized design does not support a like-for-like treatment comparison. Although the registry describes several clinical groups, those groups differ by diagnosis, age, or relapse timing and are not randomized controls. The registry record does not report a comparator group assigned to receive an alternative regimen, so treatment contrasts cannot be interpreted causally from the group labels.

The registry describes bortezomib in combination with re-induction chemotherapy and lists bortezomib among the interventions. The arm descriptions provide chemotherapy blocks but do not give a bortezomib dose or a detailed administration schedule. The detailed statistical analysis plan, sample-size justification, interim analyses, multiplicity strategy, and missing-data procedures are not reported in the registry record.

Safety interpretation is also limited by absent details. The record gives group-level counts and selected serious-event term percentages, but does not state the denominator for those term percentages in the information summarized. Group-level death counts are not reported. The available safety figures should therefore be treated as descriptive rather than as a comparative assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma — NCT00873093.
• Registry record last updated 2017-01-27; status last verified 2016-11.
• Results first posted 2017-01-27.
• 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

NCT00873093 is a completed Phase II pilot trial sponsored by the National Cancer Institute (NCI). The registry reports enrollment of 148, a start of 2009-03, and primary completion in 2014-09. The study is listed as non-randomized, unmasked, and single-group.

The trial concerns bortezomib with intensive re-induction chemotherapy for young patients with relapsed ALL or LL. Its primary endpoint is the percentage achieving complete response at the end of Block 1, measured on Day 36, among eligible and evaluable pre-B ALL patients age <= 21 years with relapse < 36 months from diagnosis. Minimal residual disease outcomes at the ends of Blocks 1, 2, and 3 are listed as secondary outcomes.

The registry record does not report the primary outcome result, its analysis denominator, or any statistical analyses. It also does not report a trial-specific sample-size justification, statistical analysis plan, multiplicity approach, or missing-data method. Adverse-event counts are listed by clinical group, but they do not create a randomized safety comparison.