Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults (NCT01462253), a na phase 2 study. The primary outcome is The Primary End-point is the Number of Patients in CR After Induction Therapy..

2. Clinical Question

3. Trial Design

This was a prospective, multicentric pilot study in adults with acute lymphoblastic leukemia described as refractory or in first bone marrow relapse. The registry classifies it as phase II and single-group. Enrollment is listed as 35. The recorded start was 2012-10, primary completion was 2017-03-11, and status is completed.

The intervention was clofarabine plus cyclophosphamide, used as salvage therapy. The stated purpose included assessing complete remission and concurrently evaluating biological responses in leukemia cells, including minimal residual disease, apoptosis, DNA cell damage, and pharmacogenomics. These aims describe the study’s scope; they do not establish that results for each biological measure were reported.

Because the study had one treatment group, its design can describe outcomes observed among participants treated with the combination, but it cannot directly estimate a treatment contrast against a concurrent control. There was no masking. Random assignment and allocation between groups do not apply to this single-group design. A control treatment, comparator population, and comparative allocation procedure are not reported in the registry record.

The primary endpoint was the number of participants in complete remission after induction therapy. The assessment timing depended in part on response: the record gives day +28 from the start of cycle 1, with an additional assessment after cycle 2 for participants with partial remission proceeding to that cycle. Secondary outcomes include toxicity of grade 2 or greater, minimal residual disease response in remission, disease-free survival, overall survival, and cumulative incidence of relapse. The registry lists six outcome measures, but no outcome analysis records.

The registry record does not report the protocol’s sample-size justification, planned enrollment rationale, interim analyses, detailed analysis populations, or full statistical analysis plan. Any planning illustration based on an observed effect should be distinguished from the design actually used: it is not a record of the trial’s intended design calculation or an estimate of observed power.

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 The Primary End-point is the Number of Patients in CR After Induction Therapy., measured over At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR.

The primary endpoint is a count: the number of participants who achieved complete remission after induction therapy. The registry defines remission through the disappearance of clinical and laboratory signs of acute lymphoblastic leukemia, together with specified blood-count and bone-marrow findings. The bone-marrow criteria include blast-cell content below 5%, with no cells clearly leukemic, and cellularity in the normal or slightly hypocellular range with evidence of trilineage hemopoiesis. The record also states that a participant must be transfusion-free and gives neutrophil and platelet thresholds.

Assessment was scheduled on day 28 from the start of chemotherapy cycle 1, or later if clinically indicated for ill or cytopenic participants. Participants with partial remission who continued to cycle 2 were assessed again after that cycle. This timing and response-dependent follow-up matter when interpreting the endpoint: the observation point was not identical for every participant described by the assessment rules.

A remission count is a clinically interpretable way to describe the observed response in a single treatment group. It does not, by itself, quantify a comparative effect, because there was no concurrent control group. The registry record does not report the number achieving remission, the denominator used for this endpoint, or an estimate of remission frequency. Those primary-result details are therefore not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The design and posted results call for several distinctions between describing a group, estimating uncertainty, and making a causal comparison. General statistical concepts are explained below; they do not imply that the registry record reports a particular analysis.

What does a single-group study estimate?

In general, a single-group study can count participants who meet an endpoint and describe the distribution of outcomes among those enrolled or assessed. For a binary endpoint such as complete remission, the count depends on a clearly defined numerator and denominator. A proportion can be estimated only when both are available and the analysis population is specified. The registry record gives the endpoint definition and lists overall enrollment, but does not report the primary remission count or its denominator. A remission proportion therefore cannot be reconstructed from the posted results.

A treatment comparison requires a reference outcome under another condition, such as a concurrent control group. In a randomized study, allocation can help make treatment groups comparable on average. This study is recorded as single-group, without allocation to treatment groups. Consequently, any observed response would be a description of outcomes during treatment, not a randomized estimate of how outcomes differ because of the treatment.

How should uncertainty be understood?

In general, a confidence interval gives a range of estimates compatible with the data under a specified statistical method. Its width reflects factors such as the amount of information and the variability of observations. For a remission count, interval estimation also depends on the denominator and on the chosen method. Neither a confidence interval nor a point estimate for the primary endpoint is reported in the registry record. No precision claim about remission can therefore be made from that record.

A p-value, in general, measures how unusual data would be under a specified null model and assumptions. It does not measure the probability that a treatment is effective, and it does not show the size or clinical importance of an effect. The registry record contains no analysis records, so no inferential p-value for the primary endpoint is reported. With no control group, a test of a remission count against a benchmark would also require a prespecified reference value and a method; these are not reported in the registry record.

What do the sample-size illustrations mean?

General sample-size calculations describe how much information a future study might need under chosen assumptions. The planning illustration associated with these results is computed from an observed effect, uses a two-sided significance level of 0.05, assumes equal allocation between two arms, and uses a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These are planning assumptions, not evidence that the original single-group study was designed with those assumptions. In particular, an equal-allocation, two-arm illustration does not match the recorded single-group design.

Such illustrations are not observed power. Observed power is not a substitute for reporting an effect estimate and its uncertainty: after results are known, a calculation based on the observed effect largely recasts the result and can be misleading about how informative the data are. Planning figures are hypothetical and depend on assumptions about the effect, significance level, allocation, and statistical approximation. The registry record does not report the trial’s own sample-size justification or a target effect used in its original planning.

For time-to-event outcomes, a general planning method may be based on the total number of events rather than participants per arm. For other outcomes, a planning illustration may express participants per arm for 80% power or another stated target. Those quantities are design illustrations, not observed participant counts or outcome results. No numerical planning results are reported in the registry record itself, and no such illustration should be read as an analysis of the trial’s observed efficacy.

Why can over-dispersion matter?

In general, over-dispersion occurs when observed variation is greater than a statistical model expects. A model that understates variation can produce uncertainty intervals that are too narrow and tests that are too optimistic. It can arise in count data when outcomes cluster or when participants differ more than the model allows. Whether over-dispersion applies depends on the outcome and model. The registry record does not report a model for the primary count or a dispersion assessment, so there is no basis to claim that over-dispersion was tested or adjusted for in this study.

How do the safety counts differ from a comparative risk estimate?

In general, a count of participants with an event describes how many in a stated group experienced at least one qualifying event. It is not the same as the total number of event episodes, and it is not automatically an incidence rate over time. A comparative risk estimate would require comparable groups and a defined analysis. The registry lists 7 participants with serious adverse events and 12 with other adverse events, each among 27 at risk. These are descriptive entries for the treatment group, not comparative estimates. The registry does not report event follow-up time or a causal comparison.

The statistical interpretation is therefore constrained by what the record actually reports: a single-group design, an endpoint definition, enrollment and safety entries, and no analysis records. General methods can explain what estimates would mean, but cannot supply missing outcome counts, uncertainty measures, or protocol choices.

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("Clofarabine + Cyclophosphamide")
n      <- c(27)
events <- c(9)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Clofarabine + Cyclophosphamide  27  9  33.3  16.5  54.0  18.6  52.2  18.6  52.4

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when a study evaluates several outcomes, time points, subgroups, or hypotheses. In general, testing many hypotheses can increase the chance of at least one apparently unusual result if no adjustment or hierarchy is prespecified. A multiplicity strategy may designate a primary endpoint, define secondary questions as supportive or exploratory, or adjust inference across a family of tests. The registry identifies a primary remission endpoint and lists secondary outcomes, but a multiplicity procedure, testing hierarchy, or family of confirmatory hypotheses is not reported in the registry record.

The registry lists six outcome measures and no analysis records. It does not provide an analysis population for the remission endpoint, explain how participants with missing endpoint assessments were handled, or report whether any participants were excluded from an efficacy analysis. Missing-data methods, imputation procedures, and sensitivity analyses are not reported in the registry record. The assessment description allows a later bone-marrow examination when clinically indicated for ill or cytopenic participants; the record does not explain how such timing or unavailable assessments entered the analysis.

These omissions matter because a count can change depending on who is included and how missing outcomes are classified. Without an endpoint denominator, analysis population, and missing-data approach, the primary result cannot be reconstructed or assessed for sensitivity to incomplete observations. The record also does not report interim analyses, early-stopping rules, or a full statistical analysis plan. Their use or absence cannot be inferred from the posted information.

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

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: septic shock (7.4%), bradycardia (3.7%), atrial fibrilation (3.7%), pneumonitis (3.7%), cytomegalovirus infection (3.7%).

The safety group is labeled clofarabine plus cyclophosphamide. The registry lists 27 participants at risk, 7 with serious adverse events, 12 with other adverse events, and 4 deaths. These are descriptive counts in the posted record. The record does not explain the relationship between the 27 safety participants and the 35 listed for enrollment, nor does it report a detailed safety analysis population.

The serious-event terms listed are septic shock at 7.4%, bradycardia at 3.7%, atrial fibrilation at 3.7%, pneumonitis at 3.7%, cytomegalovirus infection at 3.7%, and Klebsiella sepsis at 3.7%. The record does not specify whether the listed terms are mutually exclusive, whether a participant could contribute more than one term, or the event counts behind each percentage. The percentages should be read as registry entries, not as estimates of comparative risk.

Serious adverse events are not synonymous with all adverse events, and the “other” event count should not be added to the serious count without knowing the registry’s coding rules and overlap. The record does not report attribution to treatment, event timing, duration, severity details beyond the serious classification, or exposure-adjusted rates. The deaths are listed without cause or treatment relationship. These figures alone cannot establish causality or characterize the full safety profile.

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

The registry record describes a prospective phase II pilot study of clofarabine and cyclophosphamide for adults with refractory or first bone marrow relapse acute lymphoblastic leukemia. Its primary question is whether participants achieved complete remission after induction therapy, using a stated clinical and bone-marrow definition and specified assessment timing. Those details identify what the study intended to measure.

The primary remission result itself is not reported in the registry record. There is no posted remission count, denominator, effect estimate, or uncertainty interval. Therefore, the record does not establish the observed remission frequency or its precision. It also does not permit a comparison with another treatment, because the design had one group and no concurrent control.

The posted safety entries do show that the registry recorded serious and other adverse events and deaths among the safety group. They do not, without event attribution and fuller context, determine whether those events were caused by the treatment. The entry for 7 participants with serious adverse events among 27 at risk and the listed event terms should be interpreted as descriptive records, not as comparative safety estimates.

The study’s stated biological aims and its listed secondary outcomes indicate a broader set of questions than the primary remission endpoint alone. However, the registry has no analysis records, and numerical results for those outcomes are not reported in the registry record. Their mention in the study description is not evidence that a particular biological or survival effect was observed.

In general, a single-group result can be useful for describing what occurred in the participants who were studied, but it cannot separate treatment effects from other explanations. Here, the missing primary result further limits even that descriptive assessment. The information should not be taken to show that the treatment is effective or ineffective. It documents the study’s design and selected safety counts while leaving key efficacy and analysis details unavailable.

14. Why This Trial Matters Statistically

This study illustrates why endpoint definitions and endpoint results must be read separately. The registry gives a detailed definition of complete remission, including clinical, blood-count, and bone-marrow features, as well as the planned assessment timing. Yet the actual remission count and denominator are not reported in the registry record. A precise definition makes an outcome interpretable, but it cannot substitute for the observed data needed to estimate it.

The single-group design also clarifies the difference between an outcome description and a causal treatment effect. Even if a remission count were available, the lack of a concurrent comparator would restrict conclusions to the treated group’s observed outcomes. Statistical adjustment or a sample-size calculation cannot create a randomized comparison that the design did not include.

The different participant counts are another useful lesson in denominator discipline. Overall enrollment is listed as 35, whereas the safety group reports 27 at risk. The record does not explain this difference, and neither count should be assumed to be the denominator for the primary endpoint. Every estimate needs a clearly identified population and outcome-specific denominator.

Finally, a registry can identify outcomes and safety events while still lacking analysis records. The presence of several named secondary outcomes does not reveal their results, and event percentages do not establish causation. The statistical value of a clinical-trial record depends not only on design labels and outcome definitions, but also on transparent reporting of populations, missing-data handling, estimates, uncertainty, and analysis methods. These details are not reported in the registry record for the primary efficacy analysis.

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 most direct limitation is that the registry record does not report the primary complete-remission count, its denominator, or an analysis. This prevents estimation of the primary outcome from the posted information. The detailed remission criteria and assessment schedule do not resolve that missing result.

The single-group design has no concurrent comparator, so it cannot provide a randomized estimate of relative benefit or harm. The record also lists no masking. It does not report a protocol-based sample-size justification, statistical analysis plan, interim analyses, or analysis populations. These omissions make it difficult to determine which analyses were planned and how the reported outcomes were intended to be interpreted.

The overall enrollment of 35 and safety denominator of 27 are not reconciled in the record. The primary endpoint denominator is absent, and the registry does not explain participant flow, exclusions, or missing assessments. Because remission timing could be later for ill or cytopenic participants and after cycle 2 for participants with partial remission who continued, the handling of differing assessment times is also not reported in the registry record.

Safety reporting is limited to group counts, deaths, and selected serious-event terms with percentages. The record does not report event attribution, causes of death, exposure time, detailed event counts for each term, or the overlap between serious and other adverse events. The secondary outcome names do not come with posted analysis records or numerical results. These specific reporting gaps limit both efficacy interpretation and the completeness of safety assessment.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults — NCT01462253.
• Registry record last updated 2019-01-25; status last verified 2018-08.
• Results first posted 2019-01-25.
• 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 record describes a completed, prospective, multicentric phase II pilot study of clofarabine and cyclophosphamide as salvage therapy for adults with refractory or first bone marrow relapse acute lymphoblastic leukemia. It lists enrollment of 35 and identifies complete remission after induction therapy as the primary endpoint, with assessment at day +28 from the start of cycle 1 and after cycle 2 for participants with partial remission proceeding to that treatment.

The primary remission count and denominator are not reported in the registry record, and no analysis records are listed. The safety group lists 27 participants at risk, 7 with serious adverse events, 12 with other adverse events, and 4 deaths. The registry does not reconcile the safety denominator with overall enrollment or report treatment attribution for the events. The design has one group and no concurrent comparator, limiting causal interpretation.