High-dose Sequential Chemoimmunotherapy for B-cell Lymphomas With Central Nervous System Involvement: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for High-dose Sequential Chemoimmunotherapy for B-cell Lymphomas With Central Nervous System Involvement (NCT00801216), a na phase 2 study. The primary outcome is Event-free Survival.

2. Clinical Question

3. Trial Design

The registry describes a prospective phase 2 study of high-dose sequential chemotherapy and rituximab for patients with systemic B-cell lymphoma and central nervous system involvement at diagnosis or relapse. The trial is marked completed, with enrollment of 40. The recorded start is 2007-01 and primary completion is 2013-01. These dates describe the registry record; they do not supply information about the duration of follow-up for each participant.

The design is single group, with allocation listed as not applicable and masking listed as none. No concurrent comparison arm is described. The intervention is named high-dose sequential chemotherapy and autologous transplant. Its description specifies two courses of methotrexate 3.5 g/mq on day 1, cytarabine 2 g/mq twice a day for two days, rituximab 375 mg/mq on days 3 and 11, and intrathecal liposomal cytarabine 50 mg on day 6. The record then describes cyclophosphamide 7 g/mq plus rituximab 375 mg/mq and intrathecal liposomal cytarabine in case of response. The text labels the first intrathecal cytarabine dose as Phase I.

The registry summary states that the trial would assess activity and feasibility of a high-dose methotrexate-based combination. It describes the rationale as using selected drugs with anti-lymphoma activity at high doses to increase blood-brain barrier penetration and central nervous system bioavailability, and to reduce potential cross-resistance. This is the stated rationale, not a finding that those aims were achieved.

Secondary outcomes listed are time to progression, overall survival, tolerability and neurotoxicity. The record lists five outcome measures overall and no posted analysis entries. It does not report a comparator, a randomization procedure, a masking procedure beyond none, or a sample-size justification.

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.

Before assignment: 40 patients were registered, but only 38 patients met the inclusion critaria and was treatted

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: No Event registered at a 2ys follow-up of the population included

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 Event-free Survival, measured over 2-year.

The primary endpoint is titled event-free survival and has a 2-year timeframe. Its description defines success as having no new pathological events during a 2-year follow-up period. The population description similarly refers to no event registered at a 2-year follow-up. In this record, the endpoint is expressed as a count of participants, so its direct interpretation would be the number meeting that no-event definition.

Event-free outcomes can capture whether participants remain free of specified events over follow-up. In general, a time-to-event endpoint can also use information about when events occur, not only whether an event was observed by a particular follow-up point. That distinction matters because a participant whose observation ends before the specified follow-up may not have a known status for the full period. A time-to-event analysis usually needs event times and information about censoring. Those details, along with the number meeting the endpoint, are not reported in the registry record.

The phrase “new pathological events” is not further defined in the posted description. The record therefore does not make clear which events count, how recurrence or progression is handled, or how deaths are incorporated into this primary endpoint. Without a reported count or analysis, the endpoint definition alone does not establish the observed event-free outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with the design. A single-group study describes outcomes in a treated group. It does not provide the direct between-group contrast that a randomized trial can use to compare outcomes under different assigned treatments. When there is no concurrent control group, observed outcomes can be affected by factors other than the intervention. This limits causal interpretation, even if the outcome itself is measured consistently.

What does event-free survival represent?

In general, an event-free survival endpoint tracks the time until a defined event, or until the end of follow-up if no event is observed. The meaning depends on the event definition, follow-up rules and handling of participants whose event status is unknown when observation ends. The registry record describes the primary outcome as no new pathological events at 2-year follow-up, and identifies its measure as a count of participants. It does not provide an event count, individual event times, censoring information or a more detailed definition of pathological events. The posted record therefore does not support reconstruction of a time-to-event curve or an estimate of the proportion meeting the endpoint.

A confidence interval, in general, expresses the uncertainty around an estimated quantity under a statistical model. It is not a guarantee that the true value lies within a particular interval. Its width reflects such factors as the amount of information and the variability in the data. No confidence interval for the primary endpoint is reported in the registry record, and without an endpoint estimate there is no reported interval to interpret. The absence of an interval is not evidence of high precision.

Why does the design affect interpretation?

Random assignment, when used, helps make treatment groups comparable on average with respect to factors that may affect outcomes. This study is recorded as single group, with allocation not applicable. There is therefore no randomized treatment contrast to interpret. A description of outcomes after the regimen cannot by itself show what would have happened to the same participants under another treatment or without the regimen. Differences from outcomes in other populations would also require care, because the registry record does not establish that populations, follow-up or outcome definitions are comparable.

Masking is recorded as none. In general, masking can reduce the possibility that knowledge of treatment assignment influences outcome assessment or reporting, particularly for outcomes that require judgment. The practical importance depends on how outcomes are defined and assessed. The record does not describe outcome adjudication procedures, so the potential influence of unmasked assessment cannot be evaluated for this trial.

How should the planning assumptions be read?

In general, a sample-size calculation uses assumptions about the outcome, variability, effect to detect, statistical test and desired power. It is a planning exercise, not a result observed in participants. A calculation based on an observed effect is especially dependent on the estimate used: an unstable observed effect can produce an unstable planning illustration. Such a calculation does not establish that the study had a particular probability of detecting an effect after the fact, and it is not observed power.

The registry describes planning illustrations based on a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and effects expressed as fractions of an observed effect. For time-to-event outcomes, it says the planning calculation concerns total events; for other outcomes, it concerns participants per arm. These are stated calculation assumptions, not a description of the actual single-group study design. The registry does not report its own sample-size justification. No planning count should be interpreted as an observed enrollment result or as proof that the actual trial could detect a particular effect.

For count outcomes, a model may need to account for over-dispersion when variability exceeds what a simpler model expects. In general, ignoring over-dispersion can make standard errors too small and uncertainty appear narrower than it is. This trial’s primary measure is a count of participants, but the record does not report an over-dispersion assessment or model. It also does not provide enough information to determine whether an over-dispersion issue arose.

What can the posted safety counts establish?

Counts and percentages answer different questions, and each needs a clear denominator and definition. The adverse-event entry lists 38 participants at risk, with 4 affected by serious adverse events and 3 affected by other adverse events. The record does not define the observation window or clarify whether these counts refer to participants with at least one event or to event episodes. The field describes participants, but detailed event-level data are not posted.

The group also lists 22 deaths, while death appears among the top serious terms with 10.5%. The registry does not explain whether the term percentage uses the same denominator, reporting window or event definition as the death count. Those entries therefore cannot be combined into a new rate or treated as interchangeable estimates. Nor do the entries establish whether a reported event was caused by the intervention. Attribution and timing are not reported.

Finally, statistical analysis depends on the population included, the handling of missing observations, outcome definitions and the analysis plan. The record lists no analysis entries and does not report these details for the primary outcome. Consequently, there is no basis for identifying an intention-to-treat or per-protocol analysis, assessing missing-data methods, or checking whether a stated statistical model was appropriate. General statistical principles can explain what such choices mean, but they cannot fill in the trial-specific information that is absent from the registry 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("High-dose Sequential Chemoimmunotherapy")
n      <- c(38)
events <- c(16)
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  High-dose Sequential Chemoimmunotherapy  38  16  42.1  26.3  59.2  27.9  57.8  27.8  57.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists event-free survival as the primary outcome and names time to progression, overall survival, tolerability and neurotoxicity as secondary outcomes. Considering several outcomes can raise the issue of multiplicity: when many statistical tests are performed, the chance of at least one apparently notable result can increase. In general, a prespecified analysis plan may define which outcomes are primary and whether any adjustment or hierarchical testing will be used. The registry record does not report such a plan, multiplicity adjustments, or results for the secondary outcomes. It also lists no posted analysis entries, so it is not possible to determine which tests, if any, were performed or how they were interpreted.

The record does not describe missing-data procedures, exclusions from the analysis, or the population used for the primary endpoint. It does not say whether participants were analyzed according to an intention-to-treat principle, whether a per-protocol population was used, or how participants without complete follow-up were handled. Those details matter for an endpoint defined at 2-year follow-up, because status may be unknown when follow-up is incomplete.

Enrollment is listed as 40, while the safety group lists 38 at risk. The record does not explain why these counts differ or whether the primary-outcome population also differs. The distinction cannot be resolved by assuming that one number is the appropriate denominator for every analysis. Missingness, exclusions and analysis populations are not reported in the registry record.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death (10.5%).

The adverse-event entry lists 38 participants at risk in the high-dose sequential chemoimmunotherapy group. It reports 4 participants affected by serious adverse events and 3 affected by other adverse events. These are participant counts, not a complete description of how many event episodes occurred, how long participants were observed, or when events arose. The registry record does not provide those details.

The group also records 22 deaths. Separately, death is listed as a top serious term with 10.5%. The record does not explain how that term percentage relates to the death count, what denominator or reporting window it uses, or whether the entries refer to the same set of events. They should therefore be read as distinct registry entries rather than combined into a new estimate. No calculation from these figures is needed to see that the record does not provide a single, fully defined mortality measure.

These safety entries do not establish causation. The record does not state whether the deaths or other events were considered related to treatment, nor does it give individual-level timing or clinical context. They describe what is recorded for the group; they do not, by themselves, quantify risk relative to another treatment or population.

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

The trial record documents a phase 2, single-group study intended to assess the activity and feasibility of high-dose sequential chemotherapy and rituximab in B-cell lymphoma with central nervous system involvement. It specifies a primary event-free survival outcome at 2-year follow-up and lists several secondary outcomes. It also reports a set of adverse-event counts.

What the record does not establish is the observed primary outcome. No number of participants meeting the event-free definition, time-to-event estimate, confidence interval or result for the secondary outcomes is posted. The registry’s description of an outcome is not itself evidence of the outcome’s result. In particular, the absence of a posted efficacy result should not be interpreted as no events, no progression, or a favorable or unfavorable effect.

The single-group design also means that outcomes among participants who received the regimen cannot be directly contrasted with outcomes under a concurrent alternative. The record does not support a causal estimate of treatment effect. Nor do the safety counts establish comparative safety or treatment attribution. The listed deaths and serious adverse-event terms need separate interpretation because their relationship and reporting basis are not specified.

More generally, a clinical trial record can identify the question, intervention, outcome definitions and some observed counts while still leaving important uncertainty about analysis and follow-up. Here, the endpoint result, analysis population, missing-data handling, detailed event definitions and statistical analysis plan are not reported in the registry record. The available information supports a description of the study design and recorded safety entries, but not a quantitative conclusion about event-free survival or a comparison of treatment effects.

14. Why This Trial Matters Statistically

This study is statistically notable because it applies a single-group phase 2 design to a population described as having systemic B-cell lymphoma with central nervous system involvement at diagnosis or relapse. Its primary outcome is event-free survival at 2-year follow-up, while its intervention description includes a sequence of high-dose chemotherapy, rituximab, intrathecal liposomal cytarabine and, in case of response, cyclophosphamide and further treatment.

The record also illustrates why outcome definitions and reported results must be distinguished. A label such as event-free survival suggests a time-to-event question, but the registry describes the measure as a count of participants with no new pathological events at follow-up. Without a posted event count, event times, censoring information or fuller event definition, readers cannot derive a time-to-event estimate or assess its precision. The statistical meaning depends on the actual endpoint and analysis details, not the title alone.

Its design makes the limits of comparison especially important. A single-group study can describe experience in the enrolled group, but it lacks the randomized concurrent contrast needed to estimate how outcomes differ between assigned treatments. This is particularly relevant when interpreting safety counts, which do not by themselves quantify comparative risks or establish that treatment caused an event.

Finally, the registry’s planning assumptions describe hypothetical calculations with two-arm equal allocation, whereas the actual design is single group. Keeping planning illustrations separate from trial design and observed results is essential: planning calculations are not trial findings and are not observed power. The record does not report a trial-specific sample-size justification or analysis plan, so statistical conclusions must remain limited to the documented design and counts.

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 registry record leaves the primary outcome without a numerical result. It identifies event-free survival at 2-year follow-up but gives no number of participants meeting the endpoint, no estimate of event-free survival, and no measure of precision. The wording “new pathological events” is not further operationalized, and the record does not describe event adjudication or how death is treated within the endpoint.

Follow-up details are also absent. The record does not report how many participants completed follow-up, whether follow-up duration varied, or how participants whose status was unknown were handled. With enrollment of 40 and a safety group of 38 at risk, the reason for the difference is not stated. Neither number should automatically be used as the denominator for the primary outcome.

The single-group design does not provide a concurrent control for comparison. The record does not describe randomization or masking, and masking is listed as none. It does not give enough information about eligibility, participant characteristics, outcome assessment or analysis populations to assess how the enrolled group relates to other populations or how outcome measurements were made.

Although adverse-event counts and deaths are listed, the record does not provide event timing, exposure duration, attribution, or an explanation of how the 22 deaths relate to death listed as a serious term at 10.5%. The secondary outcomes are named, but results are not posted. The statistical analysis plan, missing-data methods, multiplicity handling and trial-specific sample-size justification are not reported. These omissions prevent a fuller assessment of efficacy, safety and statistical precision.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: High-dose Sequential Chemoimmunotherapy for B-cell Lymphomas With Central Nervous System Involvement — NCT00801216.
• Registry record last updated 2024-12-10; status last verified 2024-11.
• Results first posted 2024-12-10.
• 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

This completed phase 2 trial is recorded as a prospective, single-group study with enrollment of 40. It evaluated high-dose sequential chemotherapy and rituximab in patients with systemic B-cell lymphoma and central nervous system involvement at diagnosis or relapse. The primary outcome was event-free survival at 2-year follow-up, described as no new pathological events. Secondary outcomes included time to progression, overall survival, tolerability and neurotoxicity.

The registry record does not post a numerical primary-outcome result or analysis entries. Its safety group lists 38 participants at risk, 4 affected by serious adverse events, 3 by other adverse events, and 22 deaths; death is separately listed among top serious terms with 10.5%. The relationship between those safety entries is not explained. The record does not report a comparator, a trial-specific sample-size justification, the statistical analysis plan, or missing-data and analysis-population details.