Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia (NCT00666588), a non-randomized phase 2 study. The primary outcome is Dose Limiting Toxicity.

2. Clinical Question

3. Trial Design

This was a phase II pilot study with a non-randomized, parallel design and no masking. The registry lists enrollment of 52 and a status of completed. The title describes children and young adults with recurrent, refractory, or secondary acute myeloid leukemia; the condition list names a range of childhood and adult acute myeloid leukemia subtypes. Detailed eligibility criteria, including the operational definition of “younger,” are not reported in the registry record.

The arm descriptions distinguish patients by prior anthracycline exposure and describe different study aims. For low prior anthracycline exposure, one arm is described as assessing efficacy with bortezomib 1.3 mg/m2 alongside idarubicin and low-dose cytarabine. The high prior anthracycline exposure arms use etoposide and high-dose cytarabine, with bortezomib at 1.0 mg/m2 or 1.3 mg/m2; their descriptions refer to feasibility or efficacy. The listed interventions also include laboratory biomarker analysis. Some arm-description text is incomplete in the registry record, so additional regimen details cannot be established from it.

Because allocation was not randomized, differences among arms may reflect who entered each arm, their prior treatment exposure, and the distinct regimens, as well as any treatment differences. The registry record does not report how participants were assigned to arms, whether assignment rules changed over the course of the study, or whether all arms were intended for direct comparison. The study therefore supports a descriptive reading of its arm-level outcome counts, not a controlled causal comparison. The record does not report a protocol-level sample-size justification or detailed analysis plan.

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.

6. Primary Endpoint

The registry lists the primary outcome as Dose Limiting Toxicity, measured over During Course 1.

The primary outcome is the number of participants with dose-limiting toxicity during Course 1. It is a binary participant-level outcome: each participant is classified according to whether dose-limiting toxicity occurred during that period, and the reported measure is a count. The registry description does not give a definition of dose-limiting toxicity, the criteria used to judge an event, or how events were attributed. Those details are not reported in the registry record.

As a general trial-design concept, an early-course toxicity endpoint can be used to characterize whether a regimen is feasible to administer at the doses under study. That makes it relevant to a phase II pilot that the registry describes as examining side effects and dose. The outcome is not itself a measure of antileukemic response, duration of response, or survival. Those questions require separate outcome definitions and results.

The registry record names the primary outcome and timeframe but does not report the number of participants who experienced dose-limiting toxicity. It also does not report a confidence interval or an analysis for this endpoint. Consequently, the endpoint’s observed frequency and its precision cannot be assessed from the posted results. The arm-level adverse-event counts are separate safety information and should not be treated as the missing primary outcome result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record identifies a binary primary outcome: whether a participant had dose-limiting toxicity during Course 1. The registry’s specified measure is the number of participants with the event, rather than a continuous measurement. As a general statistical principle, a binary outcome can be described with a count and a denominator, and an estimated event proportion can be accompanied by a confidence interval to show its uncertainty. The registry record does not report the primary outcome count, an estimate, or an interval, so these quantities cannot be interpreted for dose-limiting toxicity.

What does the non-randomized design imply?

In a randomized comparison, allocation by chance can help balance measured and unmeasured characteristics between groups. In a non-randomized study, arm membership may instead be connected to clinical characteristics, prior treatment, or decisions about the regimen. Here, arm descriptions explicitly distinguish prior anthracycline exposure, and they also describe different doses and aims. The registry record does not report the assignment process or enough detail to establish comparability. As a general statistical principle, observed differences between these arms could reflect those differences in participants or treatment context rather than a treatment effect. The record itself warns that the arms are not a like-for-like control comparison.

What can a confidence interval tell a reader?

As a general explanation, a confidence interval expresses the statistical uncertainty around an estimated quantity under a specified method and model. A narrow interval indicates greater precision under those assumptions, while a wide interval indicates less precision. An interval does not correct for bias from non-random allocation, incomplete outcome recording, or an unsuitable comparison. No confidence interval for the primary outcome is reported in the registry record. The posted serious and other adverse-event counts likewise do not include comparative intervals or an adjusted analysis.

How should arm-level counts be read?

The safety record gives numbers of participants at risk and numbers affected in serious and other adverse-event categories. Counts retain the scale of the observed data and are useful for checking how many participants are represented. They should not be mistaken for a causal estimate. A participant may experience multiple events, and the registry record does not explain whether the term-level percentages count participants, events, or another unit. It also does not specify the attribution rules used for adverse events. As a general statistical principle, event definitions, observation periods, and analysis populations affect what an adverse-event count means.

The serious-event counts are reported by arm, but no deaths are recorded as a numeric value; death counts are not reported in the registry record. The record does not give a primary dose-limiting-toxicity count, so the serious-event summaries cannot substitute for that endpoint. Nor do these summaries measure efficacy. They are descriptive safety information whose interpretation depends on details not present in the record.

What do the planning assumptions represent?

The planning illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It frames the effect to detect as a stated fraction of the observed effect. These are planning assumptions, not evidence that the trial used this design or analysis. The actual study was non-randomized and had four described arms, so an equal-allocation, two-arm illustration does not describe its allocation. As a general principle, sample-size calculations depend on assumptions about the outcome, effect size, variability, significance level, and desired power. Changing those assumptions changes the planning result.

The sample-size illustrations are not observed power. Observed power is not a substitute for interpreting the estimate and its uncertainty; planning calculations are best understood as hypothetical illustrations conditional on their assumptions. The registry record does not report its own sample-size justification, target power, or the assumptions used to choose enrollment. No numerical planning result is repeated in this explanation.

What analyses are missing?

The registry lists six outcome measures and no analyses. The named secondary outcomes concern NF-kB activity by ELISA, proteasome inhibition activity, protein expression assessed by Western blot, and feasibility of stem cell quantitation through percentage of leukemia initiation cells depleted. The record does not report their results or describe inferential methods for them. It also does not report a statistical analysis plan, model specifications, adjustment for baseline characteristics, or a plan for multiple outcomes. These are absences in the registry record, not evidence that a particular method was or was not used outside the 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("Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycl", "Bortezomib 1.0mg/m2-assess Feasibility High Anthra", "Bortezomib 1.3 mg/m2-assess Feasibility High Anthr", "Bortezomib 1.3 mg/m2-assess Efficacy High Anthracy")
n      <- c(14, 6, 6, 20)
events <- c(0, 1, 0, 0)
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  Bortezomib 1.3mg/m2-assess Efficacy-low Anthracycl  14  0  0.0  0.0  23.2  0.0  21.5  0.2  21.8
ARM  Bortezomib 1.0mg/m2-assess Feasibility High Anthra  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Bortezomib 1.3 mg/m2-assess Feasibility High Anthr  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Bortezomib 1.3 mg/m2-assess Efficacy High Anthracy  20  0  0.0  0.0  16.8  0.0  16.1  0.1  16.1

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists six outcome measures, including dose-limiting toxicity as the primary outcome. It names secondary outcomes involving NF-kB activity by ELISA, proteasome inhibition activity, protein expression assessed by Western blot, and feasibility of stem cell quantitation through percentage of leukemia initiation cells depleted. No analyses are listed, and results for these measures are not reported in the registry record.

When a study evaluates multiple outcomes or makes multiple comparisons, the chance of at least one apparently notable result can increase. As a general statistical principle, a prespecified approach to multiplicity can help readers understand how the analyses account for that issue. The registry record does not report a multiplicity adjustment or explain how results across outcomes or arms were to be interpreted. With no analyses or results posted, there is no basis to assess how multiplicity affected any finding.

The record also does not report missing-data counts, reasons for missingness, methods for handling missing observations, or analysis populations for the endpoints. It is therefore not possible to determine from the record whether each endpoint used all enrolled participants, only participants who began treatment, or another defined group. These details matter because exclusions or incomplete follow-up can change the population represented by an estimate. The absence of those details should not be read as evidence that data were missing or that a particular handling method was used; those matters are not reported in the registry record.

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: infections and infestations - other, specify (33.3%), abdominal pain (16.7%), acute kidney injury (16.7%), adult respiratory distress syndrome (16.7%), alanine aminotransferase increased (16.7%).

The registry reports serious and other adverse-event counts by arm. For serious events, the counts are 3 of 16, 3 of 6, 1 of 6, and 5 of 20. For the separate other-event category, the counts are 14 of 16, 5 of 6, 5 of 6, and 14 of 20. These are descriptive counts of participants affected, with the corresponding numbers at risk shown in the registry. They are not the primary dose-limiting-toxicity results.

The listed serious-event terms include “Infections and infestations - Other, specify” at 33.3%, and abdominal pain, acute kidney injury, adult respiratory distress syndrome, alanine aminotransferase increased, and anal pain at 16.7% each. The registry record does not explain the denominator or event-counting rules for these term-specific percentages, nor whether one participant could appear under multiple terms. These percentages should therefore be read as registry-listed summaries, not as rates that can be compared across arms or studies.

As a general statistical principle, adverse-event comparisons need consistent definitions, observation periods, and populations, along with an appropriate design. Here, the trial was non-randomized, and the arms differed in exposure group and regimen. The counts do not establish causation or support a ranking of regimens. Death counts are not reported in the registry record, and the record does not provide enough detail to reconcile adverse-event categories with dose-limiting toxicity.

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

The record establishes that a phase II pilot study was conducted to examine bortezomib combined with chemotherapy in children and young adults with recurrent, refractory, or secondary acute myeloid leukemia. It documents a non-randomized, unmasked, parallel design, enrollment of 52, a primary outcome defined as participants with dose-limiting toxicity during Course 1, and arm-level adverse-event counts. These details describe the study’s scope and the safety information entered in the registry.

The record does not establish the observed frequency of dose-limiting toxicity, because the primary outcome result is not reported in the registry record. It does not provide efficacy results, confidence intervals, or analyses that would quantify how precisely any clinical effect was estimated. The listed adverse-event counts and term percentages are not substitutes for these missing results. They do not show whether bortezomib or chemotherapy caused an event, and they do not answer whether the regimen reduced leukemia or improved a patient-centered outcome.

As a general statistical principle, a result from a non-randomized study can be affected by differences between participants and by the way treatment groups are formed. In this study, the arm descriptions distinguish prior anthracycline exposure and specify differing regimens, doses, and aims. A difference in observed counts across arms would not, by itself, isolate the effect of bortezomib dose or chemotherapy. The registry itself notes that the arms are not a like-for-like control comparison.

The record also does not report the analysis populations, missing-data handling, multiplicity approach, or detailed outcome definitions. Those omissions limit interpretation of both safety and any prospective comparison. The proper conclusion from the posted information is therefore limited: the registry describes a completed pilot study and records some adverse-event counts, but it does not report the primary outcome result or efficacy analyses needed to assess the study’s stated clinical questions.

14. Why This Trial Matters Statistically

This trial raises several statistical issues that recur in early clinical research: how to describe toxicity in a pilot study, how to interpret multiple arms without random allocation, and how much can be learned when outcome results and analysis details are absent from a registry record. The primary endpoint is a participant count over Course 1, a form of outcome that is directly relevant to the stated focus on toxicity and dose. But without its result, even a clearly named endpoint cannot answer the central safety question.

The study’s arm structure also illustrates why treatment groups should not automatically be treated as comparable. The registry describes different prior anthracycline exposure groups, regimens, bortezomib doses, and aims. As a general statistical principle, these features can be entangled with who receives each regimen. Descriptive counts can characterize what was recorded in each group, but a causal interpretation requires a design and analysis that address those sources of difference. The registry record does not report such an analysis.

The record lists several biomarker and laboratory outcomes in addition to the primary toxicity outcome. As a general principle, multiple outcomes create interpretive challenges: readers need to know which outcomes were prespecified, how they were analyzed, and whether any adjustment or hierarchy guided interpretation. Those details and the corresponding outcome analyses are not reported in the registry record. This makes it important to distinguish the existence of an outcome listing from evidence that the outcome was measured successfully or yielded a particular result.

Finally, the planning assumptions associated with sample-size illustrations should not be confused with the trial’s observed evidence. An illustration based on a two-arm, equally allocated comparison does not describe this non-randomized, four-arm study. The statistical value of the record is therefore chiefly methodological: it makes visible the design, endpoint definition, arm descriptions, and some safety counts, while also showing how missing results and analysis information constrain inference.

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 main limitation specific to interpreting this trial is that the registry record does not report the result of its stated primary endpoint, dose-limiting toxicity during Course 1. It also does not report efficacy results or analyses for the listed biomarker and laboratory outcomes. With six outcome measures listed and no analyses reported, the posted record does not permit an assessment of outcome estimates or their precision.

The non-randomized design and absence of masking limit comparisons among the arms. The arms are organized around different prior anthracycline exposure groups, treatment regimens, bortezomib doses, and stated aims. The record explicitly cautions that they are not a like-for-like control comparison. The assignment process and analysis methods are not reported in the registry record, so it is not possible to assess whether or how differences among participants were addressed.

Further interpretation is restricted by missing methodological details. The record does not report eligibility criteria in detail, the analysis populations, definitions of dose-limiting toxicity, missing-data handling, multiplicity procedures, or a statistical analysis plan. Some arm-description text is incomplete, limiting the ability to reconstruct all regimen details. The term-specific serious adverse-event percentages lack reported counting and denominator details, and death counts are not reported in the registry record.

Enrollment was 52, but the record does not provide endpoint-specific denominators or estimates for the primary outcome. Consequently, the overall enrollment figure alone cannot establish how many participants contributed to each outcome or how precise any result would be. These limitations concern what can be inferred from the registry record; they do not establish whether additional information exists elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia — NCT00666588.
• Registry record last updated 2018-05-22; status last verified 2018-05.
• Results first posted 2014-02-06.
• 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 describes NCT00666588 as a completed phase II pilot study of bortezomib with combination chemotherapy for children and young adults with recurrent, refractory, or secondary acute myeloid leukemia. Enrollment was 52. The design was non-randomized, parallel, and unmasked. Arm descriptions vary by prior anthracycline exposure, chemotherapy regimen, bortezomib dose, and stated study aim.

The primary outcome was the number of participants with dose-limiting toxicity during Course 1. Its result is not reported in the registry record. Six outcome measures are listed, but no analyses are listed. The record reports serious and other adverse-event counts by arm and selected serious-event terms with percentages, but these data do not provide a like-for-like treatment comparison. The registry does not report efficacy results, a detailed statistical analysis plan, or key analysis-population and missing-data details.