Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (NCT00104858), a na phase 2 study. The primary outcome is Overall Survival.

2. Clinical Question

3. Trial Design

This was a phase II, multicenter trial of a single treatment group. The registry records an enrollment of 66 and a completed study, with a start date of 2004-12 and primary completion on 2018-03-30. These record details describe the study’s status and accrual; they do not establish that every enrolled subject contributed to every outcome.

The treatment was a nonmyeloablative conditioning and transplant approach for patients with advanced CLL. The regimen description includes fludarabine given intravenously on days -4 to -2, rituximab on days -3, 10, 24, and 38, single-fraction low-dose total-body irradiation on day 0, and allogeneic hematopoietic stem cell transplantation on day 0. The arm description is truncated in the registry record, so the full treatment description is not reported there. Cyclosporine and mycophenolate mofetil are listed among the interventions.

In a single-group study, the observed outcomes describe participants receiving the study regimen. Without a concurrent control group, those outcomes do not by themselves estimate how the regimen compares with another treatment. Historical comparisons are identified among the secondary outcomes, but the record does not provide their results or enough detail to assess comparability.

The primary endpoint was overall survival, expressed as the number of participants surviving post-transplant at 18 months. The outcome description says 14 subjects enrolled before rituximab was added were counted toward accrual but not evaluated for outcome measures. The primary outcome result itself is not reported in the registry record. The record also lists 10 secondary outcome measures, including relapse or progression, graft-versus-host disease, treatment-related mortality, response, infections, and immune reconstitution. It reports no analyses.

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

Analysis population for the primary outcome, as defined in the registry: 14 subjects were enrolled prior to the addition of rituximab. These subjects are counted towards accrual but not evaluated with respect to outcome measures.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: Historical Controls were utilized for comparison

6. Primary Endpoint

The registry lists the primary outcome as Overall Survival, measured over At 18 months.

Overall survival is the primary endpoint, defined in the record as the number of participants surviving post-transplant at 18 months. This is a count at a stated follow-up time. It is not, as recorded, a hazard ratio, median survival time, or survival percentage. Those other forms would require additional information or a different presentation.

General: survival is often used in clinical research because it captures whether participants are alive at a specified time, regardless of the particular clinical events that preceded that status. A fixed-time count can be easy to interpret, but its meaning depends on which participants are included, how follow-up is handled, and whether all participants’ status is known at that time. Those details affect interpretation and cannot be assumed from the endpoint name alone.

The registry states that 14 subjects enrolled before rituximab was added counted toward accrual but were not evaluated for outcome measures. It does not report the number surviving at 18 months, a confidence interval, or an estimate accounting for incomplete follow-up. The outcome description therefore specifies what was intended to be counted, but the registry record does not present the primary result. No conclusion about the size or precision of the observed survival outcome can be drawn from the endpoint definition alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is limited. It identifies the study as phase II, single-group, and unmasked, with allocation marked not applicable. It names overall survival at 18 months as the primary endpoint and describes it as a participant count. It reports no analyses. A detailed statistical analysis plan is not reported in the registry record.

What does a single-group design estimate?

General: a single-group study records outcomes among participants who receive the study regimen. It can describe what happened in that group, subject to follow-up and outcome ascertainment. It does not create a concurrent counterfactual group. Without a valid comparison, differences from historical experience can be influenced by differences in participant selection, disease characteristics, care, follow-up, or outcome definitions. The registry lists a secondary comparison with historical data, but does not report the underlying data or methods.

That design distinction matters when interpreting overall survival. A count of participants alive at a specified time can describe the observed group if the denominator and follow-up status are clear. It cannot, on its own, isolate the effect of the regimen from other influences. The registry’s primary endpoint description supplies the time point and outcome type, but does not supply the result or the details needed to judge completeness of follow-up.

What does the 18-month endpoint represent?

The primary endpoint is a count of participants surviving post-transplant at 18 months. General: a fixed-time survival outcome concerns status at a particular follow-up point. It differs from a time-to-event analysis, which uses the timing of events and may account for participants whose follow-up ends before an event is observed. The record does not identify a time-to-event analysis for the primary endpoint, report censoring methods, or provide a survival curve. Those methods are not reported in the registry record.

The outcome description excludes 14 subjects who enrolled before rituximab was added from outcome evaluation, although they counted toward accrual. That is a stated analysis-population distinction. The record does not explain how the primary outcome denominator was otherwise defined, how missing or unknown survival status was handled, or whether follow-up differed among participants.

How should precision be assessed?

General: a confidence interval communicates the range of values compatible with an estimate under a specified statistical model and sampling assumptions. A narrow interval generally indicates greater precision than a wide interval. A point estimate without an interval can conceal substantial uncertainty, especially when the number of observed events or the follow-up information is limited. The registry record does not report a confidence interval or other precision measure for the primary endpoint, so its statistical precision cannot be assessed from the posted results.

General: over-dispersion is relevant when observed count variability exceeds what a model assumes. A model that ignores extra variability can understate uncertainty. The registry defines the primary endpoint as a count, but does not report a count model, a dispersion estimate, or a model-based analysis. There is no basis in the record for saying over-dispersion was present or that a particular adjustment was used.

What do planning calculations mean?

The registry describes sample-size planning illustrations based on an 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 a stated fraction of the observed effect. For time-to-event illustrations, the description says the total number of events is reported; for other illustrations, it says participants per arm. These are assumptions for planning illustrations, not evidence that the trial used a two-arm design. The actual study is recorded as single-group, and its sample-size justification is not reported in the registry record.

General: a planning calculation asks how much information a future study might need under chosen assumptions. It does not describe the information actually observed in a completed study. Such calculations are not observed power, and they do not establish that the study was adequately or inadequately sized. The record gives no trial-specific power target or justification.

Were multiple outcomes or analyses addressed?

The registry lists 10 secondary outcome measures in addition to the primary endpoint and reports no analyses. It does not report a multiplicity adjustment, a hierarchy among endpoints, prespecified subgroup analyses, interim analyses, or a statistical plan. General: when many outcomes or statistical tests are examined, the chance of at least one apparently notable result can increase. Prespecification and multiplicity methods can help readers distinguish confirmatory questions from exploratory ones, but the registry record does not state whether such methods were used.

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 (Chemotherapy and Rituximab Followed by ")
n      <- c(52)
events <- c(34)
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 (Chemotherapy and Rituximab Followed by   52  34  65.4  50.9  78.0  51.8  76.8  51.7  76.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists overall survival as the primary outcome and 10 secondary outcome measures. Those secondary measures cover survival and serious adverse events in comparison with historical data, relapse or progression, graft-versus-leukemia analyses, graft-versus-host disease, regimen-related toxicity and infections, treatment-related mortality, rituximab concentration, and complete or partial response. The record reports no analyses.

A statistical plan describing endpoint hierarchy, the number or type of statistical tests, multiplicity control, or interim analyses is not reported in the registry record. General: when researchers test many outcomes, the likelihood of finding at least one apparently notable result by chance can increase. A prespecified hierarchy or adjustment can address that issue, but none is described in the record. With no reported analysis results, there are also no reported p-values or estimates to interpret for these outcomes.

Missing-data methods are not reported in the registry record. The primary endpoint description does state that 14 subjects enrolled before rituximab was added counted toward accrual but were not evaluated for outcome measures. The record does not give the primary analysis denominator, explain how unknown survival status was treated, or describe loss to follow-up. It therefore does not support classifying the primary analysis as intention-to-treat, per-protocol, or another named analysis population.

These limitations are separate from the treatment-group safety counts, which have their own stated at-risk denominators. The record does not explain how missing adverse-event information was handled. A completed status and an enrollment count do not resolve these questions about analysis populations or outcome availability.

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: thrombotic microangiopathy, secondary to cyclosporine, resulting in renal failure requiring dialysis (1.9%), myocardial infarction (1.9%), death related to grade 4 gvhd (1.9%), death-septic shock related to acute gvhd (1.9%).

The adverse-event record lists a treatment group with 52 participants at risk for serious adverse events, of whom 4 were affected. For other adverse events, it lists 52 at risk and 22 affected. These are counts as recorded, not estimates of comparative risk. There is no concurrent control group in this single-group study.

The record lists 33 deaths for the treatment group. It does not state in this summary whether each death was attributed to treatment, the underlying disease, transplant complications, or another cause. The death count should therefore be read separately from the listed serious-event terms and not treated as a count of treatment-related deaths.

Four serious-event terms are listed: thrombotic microangiopathy, secondary to cyclosporine, resulting in renal failure requiring dialysis; myocardial infarction; death related to grade 4 GVHD; and death-septic shock related to acute GVHD. Each term is listed as 1.9%. These term entries describe reported serious events, but the record does not give event timing, duration, recurrence, or a complete account of overlap between terms and participants. The listed terms should not be added to infer a participant total.

General: an adverse-event count is most informative when read with its at-risk population, event definition, observation period, severity, attribution, and completeness of reporting. The registry supplies some counts and terms, but not all of these contextual details. The figures are safety descriptions, not a controlled estimate of excess risk.

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

The registry record establishes that a phase II, single-group study evaluated a transplant regimen involving fludarabine, radiation therapy, rituximab, and donor stem cell transplantation for advanced CLL. It identifies overall survival at 18 months as the primary endpoint and records 66 enrolled participants. The endpoint description says 14 subjects enrolled before rituximab was added counted toward accrual but were not evaluated for outcome measures.

The record does not report the number surviving at 18 months or a statistical estimate of that outcome. It therefore does not show, in the posted results, the magnitude or precision of the primary endpoint. A completed study status and a clearly named endpoint cannot substitute for the missing result.

Even if a survival count were available, the design would support a description of outcomes in the treatment group, not a randomized comparison. The absence of a concurrent control group means the study cannot, from its design alone, establish what would have occurred under an alternative regimen. The secondary-outcome title referring to historical data does not supply a reported comparison or remove the limitations of historical comparisons.

The adverse-event entries provide some counts for the treatment group, including serious and other events and deaths. They do not, on their own, establish which events were caused by treatment or how the group’s outcomes compare with another group. The listed serious-event terms and percentages also do not provide a complete account of clinical context or event overlap.

General: statistical evidence is most informative when estimates are accompanied by uncertainty measures and when the design supports the comparison being claimed. Neither the primary outcome estimate nor its precision is reported in the registry record. The available information supports a cautious account of what was planned, how the study was structured, and which safety counts were recorded. It does not support a conclusion that the regimen improved survival, failed to improve survival, or had a particular comparative safety profile.

14. Why This Trial Matters Statistically

This trial illustrates why the endpoint definition, analysis population, and reported result must be read together. The primary outcome is defined as the number surviving post-transplant at 18 months, but the registry record does not report that count. The description also distinguishes accrual from outcome evaluation: 14 subjects who enrolled before rituximab was added counted toward accrual but were not evaluated for outcome measures. Enrollment alone therefore does not describe the primary endpoint’s analysis population.

The design is also central to interpretation. A single-group phase II study can characterize observed outcomes in participants receiving a regimen, but it does not provide a randomized concurrent comparison. A historical comparison, which is named among secondary outcomes, would require careful attention to whether the populations, follow-up, and outcome definitions are comparable. Results and methods for that comparison are not reported in the registry record.

The record’s safety entries show another statistical reading issue: counts for events and deaths require context about attribution, follow-up, and overlap. A count of deaths is not automatically a count of treatment-related deaths, and event-term percentages should not be combined into a participant total.

Finally, the record lists multiple secondary outcomes but no analyses and no reported statistical plan. That absence limits assessment of endpoint prioritization, multiplicity, missing data, and precision. The trial is statistically informative as an example of how design and reporting determine what can be concluded: the registry identifies a clinical question and some descriptive safety information, while leaving the primary outcome result and important analytical details unreported.

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 details needed to interpret the primary endpoint are not reported in the registry record. These include the number surviving at 18 months, the denominator used for that analysis, a confidence interval or other precision measure, the handling of participants with unknown survival status, and the completeness of follow-up. The endpoint description does identify 14 subjects who were not evaluated for outcomes because they enrolled before rituximab was added, but does not provide a fuller account of the analysis population.

The study has no concurrent randomized comparator. The record names historical comparisons among secondary outcomes but does not report their data, methods, or results. Consequently, it is not possible from the record to assess how historical participants were selected or whether their outcome definitions and follow-up were comparable. The single-group design also limits causal interpretation of any descriptive outcome.

The treatment arm description is truncated after its final sentence, so the full regimen details are not reported in the registry record. The record lists 10 secondary outcome measures and no analyses. It does not report a statistical analysis plan, multiplicity approach, interim analyses, sample-size justification, missing-data methods, or endpoint hierarchy. These omissions limit assessment of how outcomes were planned and analyzed.

Safety reporting includes at-risk counts, affected counts, deaths, and selected serious-event terms, but does not fully describe event timing, attribution, recurrence, or the relationship between terms and affected participants. The record also does not explain the relationship between deaths and the separate serious-event listings. These limitations prevent a complete comparative or causal safety assessment from the listed figures alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fludarabine Phosphate, Radiation Therapy, and Rituximab in Treating Patients Who Are Undergoing Donor Stem Cell Transplant Followed by Rituximab for High-Risk Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma — NCT00104858.
• Registry record last updated 2019-07-11; status last verified 2019-06.
• Results first posted 2019-07-11.
• 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 records a completed phase II, multicenter, single-group study of nonmyeloablative conditioning and donor hematopoietic cell transplantation for advanced CLL. The regimen included fludarabine, radiation therapy, rituximab, and donor stem cell transplantation; cyclosporine and mycophenolate mofetil are also listed. Enrollment was 66.

Overall survival, defined as the number surviving post-transplant at 18 months, was the primary endpoint. The record states that 14 subjects enrolled before rituximab was added counted toward accrual but were not evaluated for outcome measures. The primary outcome count and its precision are not reported in the registry record. The record lists 10 secondary outcomes and no analyses.

Safety entries list 52 at risk and 4 affected for serious adverse events, 52 at risk and 22 affected for other adverse events, and 33 deaths. The study has no concurrent randomized comparator, limiting comparative interpretation of its outcomes.