Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders (NCT00397813), a non-randomized phase 2 study. The primary outcome is Number of Patients With HCT Failure..

2. Clinical Question

3. Trial Design

This was a phase II, non-randomized, single-group trial sponsored by Fred Hutchinson Cancer Center. The registry records enrollment of 77 and lists the trial status as completed. The recorded start is 2006-01, and primary completion is recorded as 2017-09. No masking was used. The study examined total-body irradiation dose escalation alongside fludarabine phosphate and donor peripheral blood stem cell transplantation for patients with myelodysplastic syndromes or myeloproliferative disorders.

The registry describes two disease-based arms, each with planned dose levels of 300 cGy, 400 cGy and 450 cGy. Arm A was for patients with MPD or MDS-RA/RARS; Arm B was for patients with MDS-RAEB or CMML. The conditioning regimen included fludarabine phosphate IV on days -4 to -2 and total-body irradiation on day 0, followed by filgrastim-mobilized PBSC infusion on day 0. Cyclosporine and mycophenolate mofetil are listed as interventions, consistent with the registry’s description of post-transplant immunosuppression.

The record states that no patients were enrolled on arms A2 and A3 because dose escalation was never triggered. That statement is specific to those arms; the registry’s adverse-event record lists participants in Arm B Dose Levels 2 and 3. Because the study was non-randomized and did not include a randomized control group, dose-level groups are not equivalent to randomized treatment groups. Differences between them could reflect disease category, dose-escalation decisions or other factors, and the registry does not report an adjusted comparison. A protocol description or rationale for the escalation decisions is not reported in the registry record.

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: No patients were enrolled on arms A2 and A3 because dose escalation was never triggered.

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: No patients were enrolled on arms A2 and A3 because dose escalation was never triggered.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Patients With HCT Failure., measured over 200 days.

The primary endpoint was the number of patients with HCT failure within 200 days of transplant. The registry defined failure as either graft rejection, specified as < 5% donor T-cell chimerism, or disease progression within 200 days. This combines a transplant-related event with disease progression into one endpoint. It is intended to capture failure of the transplant strategy during a specified period after transplantation, rather than describing only one component such as rejection or progression.

Using a defined timeframe makes the outcome interpretable in relation to the post-transplant period named in the protocol record. The count would describe how many patients met either part of the definition, but it would not, by itself, show which component occurred or when within the timeframe it occurred. Component-specific results would be needed to distinguish graft rejection from progression; those results are not reported in the registry record.

The registry lists the endpoint and its definition but does not report the observed count, denominator for the endpoint analysis, or an estimate of uncertainty. It also does not report the number of patients assessed at the endpoint or details about how incomplete follow-up was handled. Therefore, the endpoint definition can be described, but its observed frequency and precision cannot be evaluated from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a phase II, non-randomized, single-group dose-escalation study. Those design labels matter when reading the results. Random allocation can help balance measured and unmeasured characteristics across groups; without it, differences between groups may reflect their composition or the decisions that led to treatment assignment. Here, the arms were also organized by disease category, so the dose groups are not interchangeable comparison groups.

What does non-randomized allocation imply?

In a randomized comparison, chance determines which eligible participants receive each study option. In a non-randomized study, assignment follows another process. That process may create groups that differ before treatment, whether or not those differences are fully recorded. As a general statistical principle, a difference in outcomes between non-randomized groups does not by itself establish that the treatment difference caused the outcome difference. The registry does not report a randomized control group or an adjusted dose comparison.

How should the dose levels be read?

The registry lists planned total-body irradiation levels of 300 cGy, 400 cGy and 450 cGy in each disease-based arm. It states that no patients were enrolled on arms A2 and A3 because dose escalation was never triggered. This is important context: an unfilled dose group cannot provide an observed outcome estimate for that dose. The adverse-event record does list observations in Arm B Dose Levels 2 and 3, so the statement about no enrollment on A2 and A3 should not be generalized to all higher-dose groups. The registry does not explain the dose-escalation decision process in enough detail to reconstruct it.

What does a count endpoint tell the reader?

The primary endpoint is a count of patients meeting a composite definition of HCT failure within 200 days. A count is a direct description of observed events, but it requires an appropriate denominator to convey frequency. A count without the number assessed cannot establish the proportion affected. The endpoint also combines graft rejection and disease progression. As a general statistical principle, a composite endpoint can summarize several clinically relevant events, but its overall count does not reveal which component contributes most. Component-specific counts are not reported in the registry record.

Why does uncertainty matter?

An estimate describes the observed data; an interval estimate describes the range of values reasonably compatible with those data under a statistical model. Wider intervals indicate less precision, while narrower intervals indicate greater precision. This is general statistical interpretation, not a finding from this trial. The registry does not report an estimate or confidence interval for the primary endpoint, so its precision cannot be assessed. Nor does the record report a test result or an analysis method for that endpoint.

What can adverse-event counts establish?

Adverse-event counts describe recorded events in the groups and categories used by the registry. They are not automatically comparable rates. To interpret a rate, readers need a clear definition of the event, an appropriate denominator, and clarity about the observation period and whether participants could contribute more than one event. The registry labels counts of participants at risk and affected for serious and other events, but does not provide a full statistical comparison. Its listed serious-event terms and percentages are descriptive registry entries rather than evidence of a causal difference between dose levels.

General statistical principle: sparse counts can be highly variable, and a small change in the observed count can meaningfully alter a rate. This is one reason to consider uncertainty rather than focusing only on the point estimate. No uncertainty estimates for the adverse-event counts are reported in the registry record.

What does the registry say about analysis methods?

The registry has no analysis entries. It does not report a statistical analysis plan, a sample-size justification, interim analyses, or methods for handling missing data. These omissions do not establish what investigators did outside the registry; they mean those details cannot be assessed from the registry record. No model, adjustment strategy or hypothesis-testing procedure for the primary endpoint is reported.

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("Arm A - Dose Level 1", "Arm B - Dose Level 1", "Arm B - Dose Level 2", "Arm B - Dose Level 3")
n      <- c(36, 12, 5, 24)
events <- c(4, 5, 3, 2)
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  Arm A - Dose Level 1  36  4  11.1  3.1  26.1  4.4  25.3  4.5  25.4
ARM  Arm B - Dose Level 1  12  5  41.7  15.2  72.3  19.3  68.0  19.2  68.4
ARM  Arm B - Dose Level 2  5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2
ARM  Arm B - Dose Level 3  24  2  8.3  1.0  27.0  2.3  25.8  2.5  26.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and secondary outcomes covering infections, engraftment, progression-free survival, and relapse/progression. It does not report analysis entries for these outcomes. A multiplicity strategy—how interpretation is controlled when several outcomes or comparisons are examined—is not reported in the registry record. Without that information, it is not possible to assess whether any testing plan accounted for the number of outcomes or analyses.

The primary endpoint is a composite of graft rejection and disease progression within 200 days. The record does not report separate results for those components, so readers cannot determine their individual contributions to the composite. It also does not report an endpoint analysis denominator, missing-outcome counts, or the approach used for participants whose outcome status was unavailable.

Analysis populations are not described. The registry does not report whether the primary analysis included all enrolled participants, only those who received the transplant, or another defined group. It does not report exclusions or reasons for exclusion from outcome analyses. These details are needed to understand whom an endpoint estimate represents and how incomplete follow-up might affect it.

Sample-size justification and interim-analysis procedures are not reported in the registry record. Their absence from the registry does not establish whether such planning occurred elsewhere, but it prevents evaluation of those features from this record. With no primary endpoint result or analysis description, the statistical handling of missing data, multiplicity and analysis populations cannot be assessed.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (20.0%), lung infection (20.0%), multi-organ failure (16.7%), abdominal pain (8.3%), gvhd (8.3%).

The adverse-event record reports counts of participants at risk and affected for serious and other events, as well as deaths, by dose-level group. For example, Arm A Dose Level 1 lists 36 participants at risk for serious events and 3 affected; Arm B Dose Level 1 lists 12 at risk and 7 affected. Arm B Dose Level 2 lists 5 at risk and 2 affected, while Arm B Dose Level 3 lists 24 at risk and 4 affected. These are registry counts, not estimates from a randomized comparison.

The record also lists serious-event terms with percentages, including febrile neutropenia at 20.0%, lung infection at 20.0%, and multi-organ failure at 16.7%. Other listed terms are abdominal pain, GVHD and hypoxia, each at 8.3%. The registry does not provide enough detail alongside these terms to establish a comparative risk across treatment groups or to determine whether the same participant could contribute to multiple terms. The percentages should therefore be read as descriptive entries, not as proof of a dose effect.

Deaths are listed separately by group. A death count does not, on its own, identify cause, timing, attribution or relationship to treatment. Those details are not reported in the registry record. Differences in group counts should not be interpreted as causal because allocation was non-randomized and the groups were not like-for-like controls.

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

The registry record establishes the question the study set out to address: whether a dose-escalation approach using total-body irradiation with fludarabine phosphate and donor peripheral blood stem cell transplantation could be evaluated in patients with myelodysplastic syndromes or myeloproliferative disorders. It specifies HCT failure within 200 days as the primary endpoint and defines failure as graft rejection or disease progression within that period.

However, the record does not report the observed primary endpoint result. It does not give the number of patients who experienced HCT failure, an endpoint analysis denominator, or an uncertainty estimate. Therefore, it cannot establish the frequency or precision of HCT failure from the posted registry information. The listed secondary outcomes likewise have no reported analyses.

The trial’s non-randomized design and disease-based arms also matter. Any observed differences among dose-level groups would not, by themselves, show that irradiation dose caused the differences. The record states that no patients were enrolled on arms A2 and A3 because escalation was never triggered, while adverse-event entries are present for Arm B Dose Levels 2 and 3. These details describe the recorded study structure but do not provide a controlled estimate of dose effects.

The adverse-event entries provide descriptive counts and serious-event terms. They should not be converted into claims about comparative safety without fuller information on definitions, follow-up, analysis and group comparability. Overall, the registry supports a description of the design, treatment regimen, endpoint definition and selected safety data. It does not, as recorded, support a quantitative conclusion about the primary endpoint or a causal conclusion about dose, efficacy or safety.

14. Why This Trial Matters Statistically

This trial illustrates why an endpoint definition and an outcome result must be read separately. The registry defines HCT failure precisely enough to identify which events would count and specifies a 200-day timeframe. But a clear definition cannot substitute for the observed count, denominator and uncertainty estimate. Without those results, readers cannot assess the frequency or precision of the primary outcome.

It also highlights the interpretive challenges of dose escalation without randomization. The dose levels are embedded in disease-based arms, and the record says escalation was never triggered for arms A2 and A3. That structure is fundamentally different from a randomized comparison in which participants are assigned across treatment groups under a common allocation process. Descriptive differences between groups cannot be treated as dose effects without accounting for how participants entered each group.

The safety record offers a further statistical lesson: event counts and percentages need context. Group sizes and event definitions affect interpretation, and a list of serious-event terms is not the same as a comparative safety analysis. The registry does not report uncertainty estimates or a formal analysis of these counts.

Finally, this record demonstrates the limits of registry reporting for statistical assessment. The trial is listed as completed, but the primary result, analysis populations, missing-data procedures, multiplicity approach and statistical analysis plan are not reported. Those omissions constrain conclusions even when design and treatment details are available. The appropriate interpretation is therefore specific: the registry documents what was planned and some safety observations, but does not provide the analyses needed to quantify the primary outcome or support causal comparisons.

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 important limitation for interpreting this trial from the registry is the absence of the primary endpoint result. Although HCT failure is defined as graft rejection or disease progression within 200 days, the observed count and denominator are not reported. The record also lacks component-specific results, so it is not possible to distinguish failures due to rejection from those due to progression.

The non-randomized design limits comparisons across dose levels. The arms are disease-based, and the registry states that no patients were enrolled on arms A2 and A3 because dose escalation was never triggered. This leaves no observed participants in those specified arms and means dose-level comparisons cannot be interpreted as randomized contrasts. The registry does not report an adjusted analysis to address differences between groups.

Further limitations include the absence of a reported statistical analysis plan, sample-size justification, interim-analysis details, endpoint analysis population, or missing-data method. The registry lists secondary outcomes but no analysis entries for them. The safety record includes selected counts and serious-event terms, but does not provide a full comparative analysis, uncertainty estimates, or details on event attribution and timing. These gaps restrict both quantitative interpretation and assessment of how robust the recorded findings are.

The record’s completion status and enrollment figure do not resolve these limitations. Enrollment is not the same as the number assessed for a particular endpoint, and a completed trial status does not provide an outcome estimate. Conclusions should remain limited to the study design, endpoint definition and descriptive adverse-event information that the registry reports.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Fludarabine Phosphate and Total Body Irradiation Followed by a Donor Peripheral Stem Cell Transplant in Treating Patients With Myelodysplastic Syndromes or Myeloproliferative Disorders — NCT00397813.
• Registry record last updated 2020-01-31; status last verified 2020-01.
• Results first posted 2018-10-24.
• 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 a completed phase II, non-randomized, single-group trial of fludarabine phosphate, total-body irradiation and donor peripheral blood stem cell transplantation for patients with myelodysplastic syndromes or myeloproliferative disorders. Enrollment is recorded as 77. The study began in 2006-01, with primary completion recorded in 2017-09.

The primary endpoint was the number of patients with HCT failure within 200 days, defined as graft rejection with < 5% donor T-cell chimerism or disease progression. The registry does not report the endpoint result or analysis. It also lists secondary outcomes without analysis entries. Selected adverse-event counts and serious-event terms are recorded, but do not constitute a randomized comparison. The primary result, analysis populations and statistical methods are not reported in the registry record.