Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia (NCT00003910), a na phase 2 study. The primary outcome is Proportion of Patients With Complete or Partial Response to Treatment With MTX.

2. Clinical Question

The trial’s stated purpose was to study methotrexate with or without cyclophosphamide in patients with lymphocytic leukemia and neutropenia or anemia. The treatment sequence matters for interpreting that purpose: cyclophosphamide was reserved for patients who had not responded to methotrexate after 4 months. Outcomes among those later receiving cyclophosphamide therefore describe a selected group, rather than outcomes from a randomized comparison of the two drugs.

The registry record does not report a numerical primary response result. It also does not report the number of participants who responded to methotrexate, or a numerical confidence interval for that response proportion. Thus, the central clinical question is identifiable from the registered endpoint, but the posted record does not provide the result needed to quantify the response observed.

3. Trial Design

This was a Phase II study with a single-group model, no masking, and no allocation to separate comparison groups. The sponsor was Eastern Cooperative Oncology Group. The registry record lists enrollment of 59 and a status of terminated. The recorded start date is 1999-09-15 and the primary completion date is 2010-12-01.

The registered treatment plan began with oral methotrexate at 10 mg/m2 in divided doses once weekly. Prednisone was given orally at 1 mg/kg per day for 30 days and then tapered off in the subsequent 24 days. Patients who did not respond to methotrexate after 4 months were to receive oral cyclophosphamide at 100 mg daily in step two, with the same prednisone schedule. The registry record describes cyclophosphamide as conditional treatment following methotrexate, rather than as treatment assigned at the outset to a parallel group.

The primary endpoint was the proportion of participants with complete or partial response to methotrexate. A secondary endpoint concerned the proportion with complete or partial response to cyclophosphamide among patients who failed to respond to methotrexate. The primary endpoint specifies assessment during the first 4 months and continued follow-up at intervals thereafter. These later assessments do not change the primary endpoint’s focus on methotrexate response.

Four of the 59 participants were reported as ineligible and excluded from the primary analysis. The registry record does not report further details about eligibility decisions, participant flow, treatment discontinuation, or how many participants completed each treatment step. It also does not report a statistical analysis plan or the reason the study was terminated. These omissions limit assessment of how the planned sequence was implemented and how the analyzed population was formed.

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.

Step 1

Step 2

Analysis population for the primary outcome, as defined in the registry: Of the 59 pts, 4 were ineligible and excluded from the analysis.

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 Proportion of Patients With Complete or Partial Response to Treatment With MTX, measured over Assessed during the first 4 months, then at least every three months for two years. Then every six months until five years after study entry, and every 12 months thereafter until full study stop date..

The primary endpoint is the proportion of participants with a complete or partial response to methotrexate. A proportion expresses how frequently an outcome occurred among a defined group; it is useful for describing treatment activity in a Phase II study when the registered question is whether participants meet response criteria. The registry record specifies a 95% confidence interval as the measure of uncertainty intended for this endpoint, but does not report a numerical response estimate or interval.

The registered complete remission definition requires specified blood-count and LGL-count conditions to be met for at least four weeks. It also describes complete response in terms of CD8+ cells being less than 760/mm³. Partial response is defined as meeting at least one specified criterion in the absence of complete remission, with response lasting at least four weeks. For patients treated for severe neutropenia, the description includes improvement to over 500 neutrophils/mm3, provided that the improvement represents at least a 50% improvement.

These definitions make the endpoint a clinical classification based on laboratory measures and duration, rather than a change in a single measurement alone. A confidence interval would indicate the precision of the estimated response proportion under the analysis used. Because the numerical estimate, interval, and analysis details are not reported in the registry record, the actual response frequency and its precision cannot be assessed from the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a single-group design answer?

This study is registered as a single-group Phase II trial, with no masking and no allocation to separate comparison groups. A single-group design can describe outcomes observed after a specified treatment sequence. It does not, by itself, provide a concurrent randomized group against which to estimate a treatment contrast. In this record, the principal efficacy question is the proportion responding to initial methotrexate, not the difference between methotrexate and a separately assigned control.

The treatment sequence makes the distinction especially important. Participants who did not respond to methotrexate after 4 months were to receive cyclophosphamide. Those receiving cyclophosphamide were selected based on their response to the initial treatment, so their outcomes cannot be read as if they came from a group comparable to participants who received methotrexate alone from the start. The registry record does not report a randomized comparison of those strategies.

What does the primary proportion represent?

The primary endpoint is a proportion of participants with complete or partial response to methotrexate. The endpoint description sets out response criteria and minimum duration requirements. This approach converts clinical and laboratory observations into a categorical outcome: each participant is classified according to whether the specified criteria are met. The registry record does not report the numerical count meeting those criteria or the resulting proportion.

General statistical explanation: a proportion is an estimate based on the observed participants included in its denominator. Its interpretation depends on who was included, how response was assessed, and how participants without an assessable response were handled. Those analysis details are not reported in the registry record. Four participants were reported as ineligible and excluded from the primary analysis, but no additional accounting of missing or unevaluable endpoint assessments is given.

How should a confidence interval be understood?

The endpoint specifies a 95% confidence interval. General statistical explanation: a confidence interval describes the uncertainty associated with an estimated quantity under the method used to calculate it. It is not a guarantee that the true value lies in a particular interval, and it does not substitute for a clear description of the analyzed population. Its width depends in part on the amount of information and the observed data. Here, the numerical response estimate and confidence interval are not reported in the registry record, and the method for calculating the interval is not reported either.

A confidence interval would provide information about precision, whereas a hypothesis test would address a different question under a specified null hypothesis. The registry record does not report a primary hypothesis test or a p-value. Without a numerical estimate, interval, and analysis description, neither precision nor statistical evidence for the primary endpoint can be evaluated from the posted results.

What can be concluded from the safety counts?

The registry record lists participants at risk and participants affected for serious and other adverse events in the methotrexate and cyclophosphamide groups. These are descriptive safety summaries. They do not establish a treatment contrast, particularly because cyclophosphamide was used in a selected group after methotrexate nonresponse. The record does not describe a comparative safety analysis or provide a randomized control group.

General statistical explanation: adverse-event summaries can count participants affected, event occurrences, or event types, and those are not interchangeable quantities. The recorded group fields describe participants affected, while the listed serious terms are percentages. The registry record does not report the denominator or calculation method for the percentages attached to the serious terms, nor whether participants could contribute to more than one term. Interpretation should therefore preserve the reported categories and avoid treating them as mutually exclusive outcomes or as a direct comparison between drugs.

What analysis details are unavailable?

The registry record does not report the statistical analysis plan, the method used to estimate the response proportion, or procedures for missing outcome data. It does not report interim analyses, adjustments for multiple outcomes, or a sample-size justification. These details should not be inferred from the Phase II label or from the number enrolled. The record lists two outcome measures and no analyses, but does not explain whether additional analyses were planned or conducted outside the registry entry.

General statistical explanation: analysis choices can affect which participants contribute to an estimate and how uncertainty is calculated. Prespecification helps readers distinguish planned analyses from exploratory ones, while transparent reporting allows them to assess whether exclusions or missing observations could affect interpretation. Since these methods are not reported in the registry record, the posted efficacy information cannot be independently evaluated beyond the endpoint definitions and population statement that are recorded.

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("Methotrexate")
n      <- c(55)
events <- c(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  Methotrexate  55  0  0.0  0.0  6.5  0.0  6.5  0.0  6.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary methotrexate response endpoint and a secondary cyclophosphamide response endpoint among patients who failed to respond to methotrexate. It does not report how statistical testing across these outcomes was handled, whether any multiplicity adjustment was planned, or whether formal hypothesis tests were conducted. No numerical efficacy analyses are posted in the registry record. It would therefore be inappropriate to infer an adjustment strategy or to treat the endpoints as a set of confirmatory tests.

Missing-data handling is also not reported in the registry record. The primary population statement says that 4 of the 59 participants were ineligible and excluded from the analysis. It does not say how many participants had missing response assessments, whether any enrolled participants were otherwise excluded, or how incomplete follow-up was handled. The endpoint’s scheduled assessments do not establish the analysis rules for missed visits or unevaluable responses.

General statistical explanation: missing outcome data can affect a proportion if participants with unobserved outcomes are excluded or classified in a particular way. The direction and size of any effect depend on why data are missing and on the analysis method. A participant-flow description and explicit missing-data rules help readers assess this issue, but those details are not reported in the registry record.

The record does not report the intended analysis population beyond the statement about ineligible participants, nor does it describe a sample-size justification or interim analyses. It also does not report a protocol-based statistical plan. These omissions prevent a clear assessment of the prespecified analysis strategy, the handling of incomplete data, and the relationship between planned and posted analyses.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: neutropenia (50.8%), lymphopenia (43.8%), leukopenia (37.5%), anemia (31.2%), hyperglycemia (12.5%).

The registry record lists serious adverse-event fields for methotrexate with 59 participants at risk and 56 affected, and for cyclophosphamide with 16 at risk and 8 affected. For other adverse events, it lists 59 at risk and 56 affected for methotrexate, and 16 at risk and 6 affected for cyclophosphamide. These are group-level participant counts, not a direct randomized comparison. Cyclophosphamide was intended for participants who did not respond to methotrexate, so the groups represent different treatment experiences.

The record lists serious adverse-event terms including Neutropenia at 50.8%, Lymphopenia at 43.8%, Leukopenia at 37.5%, Anemia at 31.2%, Hyperglycemia at 12.5%, and Infection with grade 3 or 4 neutropenia at 10.2%. The denominator and calculation details for these percentages are not reported in the registry record. The listed terms should not be assumed to be mutually exclusive; an individual participant may have experienced more than one type of event, but the record does not specify this.

Deaths are not reported in the registry record. The posted safety summaries do not establish whether an adverse event was caused by treatment, and they do not provide a like-for-like safety comparison between drugs.

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

The registry record documents a Phase II, single-group treatment sequence: methotrexate was the initial treatment, and cyclophosphamide was intended for patients who did not respond to methotrexate after 4 months. It also defines a primary response endpoint and a secondary response endpoint. These details clarify what investigators planned to assess.

The record does not report the numerical primary response result, the corresponding 95% confidence interval, or the numerical secondary response result. As a result, the posted information does not quantify how often participants met the registered response criteria or how precise such an estimate would be. The absence of a posted result is not evidence that no response occurred, nor does it establish a result in either direction.

The design also limits the kinds of conclusions that could follow from any single-group outcome. Without a separate concurrent comparison group, an observed response proportion would describe the participants and treatment process studied; it would not by itself show what would have happened under a different treatment. Cyclophosphamide outcomes, if reported, would concern a subset selected for not responding to methotrexate, not an initially comparable treatment arm.

Safety counts offer descriptive information about participants affected, and the registry record lists several serious adverse-event terms with percentages. The record does not supply enough methodological detail to interpret those percentages fully, and the sequential treatment design does not support a direct drug-to-drug safety comparison. The record also does not report deaths.

Overall, the posted information supports a description of the study’s registered question, treatment sequence, eligibility exclusions, endpoint definitions, and selected safety summaries. It does not support a quantitative conclusion about efficacy or a causal conclusion comparing methotrexate with cyclophosphamide. Further outcome and analysis details are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why a registered clinical question and a reported clinical result are not the same thing. The registry record specifies a primary response endpoint, its assessment period, and response criteria, yet does not report the numerical response estimate or its confidence interval. Readers can identify what was intended to be measured, but cannot assess the observed response frequency or precision from the posted results.

It also illustrates the importance of treatment sequence in interpreting a study design. Cyclophosphamide was intended only after methotrexate nonresponse. This creates a selected later-treatment group, rather than two groups that can be treated as exchangeable for a direct comparison. The registration’s single-group model and lack of allocation reinforce that distinction.

The analysis population statement is another key statistical detail. The record reports enrollment of 59 and says 4 participants were ineligible and excluded from the primary analysis. Without further participant flow or missing-data methods, readers cannot fully trace the path from enrollment to analysis. This matters because a response proportion depends on the population contributing to its numerator and denominator.

Finally, safety counts and event-term percentages require careful reading. Counts of participants affected are not equivalent to event counts, and percentages are difficult to interpret fully without denominator and calculation details. The registered safety information is useful as a record of what was posted, but it does not create a controlled comparison. These features make the trial a useful example of how design, endpoint reporting, analysis-population transparency, and uncertainty jointly determine what can be learned from a registry entry.

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 for statistical interpretation is that numerical efficacy results are not reported in the registry record. Neither the primary methotrexate response proportion nor its 95% confidence interval is posted. The secondary cyclophosphamide response result is also not reported. Consequently, the registered clinical questions cannot be answered quantitatively from these results.

The design is single-group, with no masking and no allocation to a separate control group. It can describe outcomes observed under the registered sequence but cannot establish a randomized treatment contrast. The cyclophosphamide group is additionally defined by prior methotrexate nonresponse, so it is not comparable to an independently assigned methotrexate group.

The registry record reports that 4 participants were ineligible and excluded from the primary analysis, but does not explain those exclusions in detail or provide a complete participant flow. Missing outcome data and their handling are not reported. The analysis methods, statistical plan, sample-size justification, and interim analyses are also not reported in the registry record.

For safety, the record provides participants-at-risk and participants-affected fields, as well as percentages for listed serious event terms. It does not report the denominator or calculation method for those percentages, or whether event categories overlap. Deaths are not reported in the registry record. These gaps constrain interpretation of the safety summaries and prevent a direct comparative safety assessment.

The status is recorded as terminated, but the reason for termination is not reported in the registry record. The posted information therefore leaves uncertainty about study conduct and reporting beyond the registry entries explicitly recorded.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Methotrexate With or Without Cyclophosphamide in Treating Patients With Lymphocytic Leukemia — NCT00003910.
• Registry record last updated 2023-07-05; status last verified 2023-06.
• Results first posted 2013-05-27.
• 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 Phase II study, sponsored by Eastern Cooperative Oncology Group, examined initial methotrexate treatment for large granular lymphocytic leukemia. The registered plan included prednisone with methotrexate and cyclophosphamide for patients who did not respond to methotrexate after 4 months. The study used a single-group model, had no masking, and is recorded as terminated. Enrollment was 59; 4 participants were reported as ineligible and excluded from the primary analysis.

The primary endpoint was the proportion with complete or partial response to methotrexate, with a stated 95% confidence interval. The registry record does not report a numerical primary response result or interval. It also does not report the numerical secondary cyclophosphamide response result. Safety summaries list participants affected and several serious adverse-event terms, but denominator details for the term percentages are not reported. Statistical methods, missing-data handling, and the reason for termination are not reported in the registry record.