Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma (NCT01415752), a randomized phase 2 study. The primary outcome is Progression-free Survival (PFS) for Induction Phase.

2. Clinical Question

The registry describes a randomized, open-label, parallel, four-arm phase 2 study. The four arms vary two treatment components across two stages: whether bortezomib is added during induction, and whether maintenance consists of rituximab alone or lenalidomide plus rituximab. The primary result groups the induction arms by whether they included bortezomib, rather than reporting a separate primary comparison for each maintenance regimen.

This distinction matters when interpreting the result. The primary endpoint concerns the induction phase and combines Arms A and C for RB, and Arms B and D for RBV. It does not by itself isolate the effect of either maintenance approach or establish a separate treatment comparison for each of the four sequences. The registry lists secondary questions concerning induction response, PET-documented complete response, overall survival at 5 years since maintenance, and response during maintenance among patients without PET-documented complete response after induction. Those outcomes address different aspects of treatment and follow-up; they should not be treated as interchangeable with progression-free survival.

The record’s stated rationale is that it was not known whether adding bortezomib to rituximab and bendamustine, within the treatment sequences under study, would be more effective than the comparison regimens. The posted primary analysis offers a time-to-event comparison but does not resolve every question about the four complete treatment sequences.

3. Trial Design

This is a randomized phase 2 study with a parallel design and no masking. The registry lists an enrollment of 373 and identifies the Eastern Cooperative Oncology Group as sponsor. The study concerns previously untreated mantle cell lymphoma in older patients; its official title specifies patients aged 60 or older. The registry status is active, not recruiting.

The four arms form a two-stage treatment design. Arms A and C receive rituximab and bendamustine during induction; Arms B and D add bortezomib to those induction drugs. During maintenance, Arms A and B receive rituximab, while Arms C and D receive lenalidomide plus rituximab. The arm descriptions state that induction treatment repeats every 4 weeks for 6 courses, subject to disease progression or unacceptable toxicity. The description available for some arms is truncated, so additional regimen details are not reported in the registry record.

The primary endpoint is reported for the induction comparison, pooling the two RB arms and the two RBV arms. Each pooled group has 179 participants in the posted primary analysis. These group counts should be read as the analysis populations reported for that result, not as a replacement for the overall enrollment figure. The registry identifies the primary population as eligible and treated patients at Step 1.

Follow-up for the primary endpoint is described as assessment at baseline and every 3 months for 2.5 years, then every 6 months up to 10 years from the end of treatment, and annually up to 10 years and 6 months. The registry also lists maintenance-stage outcomes, but the detailed sample sizes in those posted results differ from the induction analysis. Randomization procedures beyond the allocation designation, stratification factors, eligibility criteria beyond the stated population, and the detailed statistical analysis plan are 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.

Induction (Step 1)

Reasons for not completing this period:

Maintenance (Step 2)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Eligible and treated patients at Step 1 (induction)

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: All randomized patients are included in this analysis.

6. Primary Endpoint

The registry lists the primary outcome as Progression-free Survival (PFS) for Induction Phase, measured over Assessed at baseline, every 3 months for 2.5 years, every 6 months up to 10 years from end of treatment, and then annually up to 10 years and 6 months.

The primary endpoint is progression-free survival (PFS), measured in years. It is defined as the time from randomization to lymphoma progression or death. A time-to-event endpoint preserves information about when an event occurs, rather than reducing follow-up to a simple count of participants who experienced progression or death.

The registry’s progression definition includes new lesions, increases in the size of previously involved disease, and imaging criteria. It specifies a new lesion greater than 1.5 cm in any axis, and increases of at least 50% from nadir in specified measures of lesion size. It also describes PET positivity requirements for lesions in typical FDG-avid lymphoma, subject to the stated exception for lesions too small for current PET systems to detect. These criteria make clear that progression is defined using both changes in disease extent and imaging findings.

PFS is used in this study because it captures either of two clinically relevant events—progression or death—over follow-up. As a general statistical point, time-to-event analysis can account for differing follow-up times and for participants whose event has not been observed by the end of available follow-up. The registry record does not report how censoring was handled in detail, the number of events, or the median follow-up. Those omissions limit how fully the precision and maturity of the PFS estimates can be assessed.

The posted result gives a median PFS and a 95% confidence interval for each pooled induction group, along with a log-rank comparison. A median describes the time by which half of the analyzed group’s event-time distribution has been reached; it is not an average and does not describe every participant’s experience.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary analysis is a time-to-event analysis. Each participant’s follow-up contributes information about the time from randomization until progression or death, if that event is observed. When an event has not occurred by the last known assessment, the observation is generally censored rather than treated as if the participant had an event at that time. This is a general explanation of time-to-event methods; the specific censoring rules used in this study are not reported in the registry record.

The posted primary summaries are medians with 95% confidence intervals. A confidence interval expresses uncertainty in an estimate under the statistical model and method used. It does not mean that 95% of individual participants’ PFS times lie within the interval. The interval pertains to the estimated median for its group. The registry does not post a confidence interval for the difference between groups, so comparison of the two median intervals cannot replace an effect estimate and its uncertainty.

The reported comparison uses a log-rank test. In general, this test compares the pattern of event timing between groups across follow-up, rather than testing only the difference between two medians. A log-rank p-value does not quantify the size of a treatment effect. A hazard ratio with a confidence interval could provide a relative time-to-event effect summary, but one is not reported for this primary comparison in the registry record. The test’s assumptions and any adjustment for covariates are also not reported.

The posted result groups participants receiving RB induction and compares them with participants receiving RBV induction. This is a pooled comparison across two maintenance assignments on each side. Pooling can address an induction contrast across the assigned maintenance plans, but interpretation depends on the study design and analysis plan. Whether the pooling was prespecified, whether interactions were considered, and whether any stratification was used are not reported in the registry record.

The record also includes recalculated, unadjusted comparisons for two maintenance-stage overall-survival contrasts. These are simple re-calculations from posted summary statistics, not the sponsor’s reported analyses. In general, a risk difference is an absolute difference between two event proportions; its confidence interval describes uncertainty around that difference. For these posted recalculations, the estimated differences are 0.001 and < 0.001, and the respective confidence intervals include zero. Such results do not establish equivalence: a confidence interval that includes zero may still include effects in either direction. The corresponding unadjusted p-values are not substitutes for a prespecified, multiplicity-controlled analysis.

The registry’s planning illustrations use the observed effect as a starting point and display scenarios for detecting stated fractions of that effect. They are planning calculations, not observed power and not the study’s own sample-size justification. For the binary outcome illustrations, the stated assumptions are a two-sided significance level of 0.05, equal allocation, and a normal approximation; the illustrations give participants per arm. Very small observed absolute differences can lead to extremely large planning requirements. That reflects the difficulty of detecting a small difference with high power under those assumptions; it does not mean that the current study had a particular level of power. The assumptions behind the original trial’s design and its sample-size justification are not reported in the registry record.

Over-dispersion is a general concern when a model assumes less variability than the data contain: standard errors may then be too small and intervals too narrow. The registry does not identify a count model or report an over-dispersion assessment for the primary endpoint, so that issue cannot be evaluated as a feature of this analysis. More broadly, the record does not give the detailed model specifications, missing-data methods, censoring rules, or analysis populations beyond the stated eligible and treated Step 1 population for PFS.

10. Analyses Reported by the Sponsor

The sponsor’s posted primary analysis is a log-rank comparison of PFS for the pooled RB and RBV induction groups. It reports p = 0.25. The registry also reports the median PFS and 95% confidence interval for each group, but does not provide a sponsor-reported hazard ratio or a confidence interval for the comparative effect. The interpretation should therefore remain tied to the posted test and group-level median estimates: the record does not show a statistically significant difference in the log-rank comparison, and it does not establish that the regimens are equivalent.

The record contains no reported sponsor analyses for the posted secondary overall-survival outcome. The risk-difference estimates and associated unadjusted tests discussed for those maintenance-stage contrasts are recalculations from the posted summary statistics, not sponsor analyses. They should be treated as descriptive and exploratory, rather than as replacements for a sponsor-reported model or a prespecified analysis.

The registry’s discrepancy indicator is false, so no conflict between a sponsor-reported primary comparison and a recalculation is identified. Where a sponsor’s own analysis is reported, it takes precedence over a simple unadjusted recalculation because it may reflect the specified analysis method. Here, the primary interpretation rests on the sponsor’s log-rank result; the secondary recalculations add context but do not carry the same evidential status.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 26 outcome measures and 2 analyses. It names several secondary outcomes in addition to the primary PFS endpoint, including induction response, PET-documented complete response, overall survival at 5 years since maintenance, and response during maintenance for a specified subgroup. The record does not report a multiplicity adjustment, a hierarchy of hypotheses, or which outcomes were designated confirmatory. Without that information, nominal results across multiple outcomes should be interpreted cautiously.

Multiplicity matters because conducting multiple comparisons increases the chance that one or more results may appear unusual by chance alone. This is a general statistical concern, not a claim that any particular result in this trial is false. An analysis plan might address it through a prespecified testing sequence or an adjustment to the significance threshold, but whether either approach was used is not reported in the registry record. The unadjusted secondary recalculations should not be treated as confirmatory evidence.

Missing-data and censoring details are also limited. For PFS, the registry describes assessment schedules and the event definition, but does not report the number of participants censored, how missing assessments were handled, or the censoring rules. For the maintenance-stage outcomes, the posted group sizes differ from the induction analysis population, but the reasons for that difference are not reported. Eligibility criteria for entering maintenance, exclusions, and handling of incomplete follow-up are not reported in the registry record.

The primary PFS population is described as eligible and treated patients at Step 1. The record does not specify whether the analysis followed intention-to-treat principles, how protocol deviations were handled, or whether other analysis populations were used. These details affect the interpretation of randomized comparisons because they define which participants contribute to each estimate.

Finally, the registry does not report interim analyses, stopping rules, a detailed statistical analysis plan, or the original sample-size justification. Their absence from the record does not establish that they were not used; it means they cannot be evaluated from the registry information available.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: lymphocyte count decreased (75.0%), neutrophil count decreased (60.3%), white blood cell decreased (42.5%), platelet count decreased (10.9%), lung infection (9.6%).

The safety record presents counts of participants at risk and counts affected by serious adverse events and other adverse events, separately for induction and maintenance groups. These are descriptive counts. The number at risk differs across groups and treatment stages, so counts should be read with their corresponding group size rather than compared as if every group had the same denominator. The registry does not provide an exposure-adjusted analysis or a formal between-group safety comparison.

For induction, the number with a serious adverse event ranges from 70 to 83 across the four listed arms, with 92 or 93 participants at risk in each arm. For maintenance, the corresponding counts range from 41 to 65 among groups with 68 to 74 participants at risk. The record also lists deaths by group, but does not state in these data whether those deaths were attributed to treatment or were caused by adverse events. They should not be interpreted as treatment-related deaths without that information.

The most frequently listed serious adverse-event terms are decreased lymphocyte count at 75.0%, decreased neutrophil count at 60.3%, decreased white blood cell count at 42.5%, decreased platelet count at 10.9%, lung infection at 9.6%, and hypertension at 7.6%. The record does not provide the event grading, duration, timing, recurrence, or detailed attribution information needed to interpret these terms beyond their listing and reported frequency. These safety data describe what was recorded; they do not by themselves establish comparative risk between regimens.

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

The primary result shows that the registry’s log-rank comparison of PFS between the pooled RB and RBV induction groups has a p-value of 0.25. The posted medians are 5.5 years for RB and 6.4 years for RBV, with the reported 95% confidence intervals for each median. The numerical difference between medians is not, on its own, evidence that adding bortezomib changed PFS. The comparison test is not statistically significant, and the record does not supply a comparative hazard ratio or confidence interval.

That result does not show that the groups have identical outcomes. A non-significant test is not an equivalence test, and the record does not report an equivalence margin or a non-inferiority framework. It also does not establish that one regimen is better or worse. The result is best understood as an uncertain comparison in the posted analysis, rather than proof for either direction.

The primary contrast pools across maintenance assignments, so it does not answer every question about the four treatment sequences. The secondary overall-survival estimates and unadjusted recalculations offer additional descriptive information, but their uncertainty and the absence of sponsor-reported secondary analyses limit their evidential weight. The listed response outcomes cannot be assessed fully because numerical results are not reported for them in the registry record.

In general, statistical results describe patterns in a study population under particular definitions and methods. They do not predict an individual patient’s outcome. The registry record also does not establish how the result applies beyond the study’s stated population or treatment setting. The findings should be read as a report of the posted comparisons and their precision, not as medical advice or a definitive judgment about treatment.

14. Why This Trial Matters Statistically

This trial is statistically interesting because its four-arm structure separates two treatment decisions across different stages: adding bortezomib during induction and choosing between rituximab alone or lenalidomide plus rituximab during maintenance. The primary analysis focuses on the induction contrast by pooling across maintenance assignments. That makes the estimand—the particular treatment contrast being analyzed—important to understand before interpreting the result.

The use of PFS also illustrates why endpoint definitions and follow-up matter. The endpoint combines progression and death, and progression is defined through specified lesion changes and imaging criteria. The result is a time-to-event comparison, not simply a comparison of response proportions. The registry gives a schedule for repeated assessment over long follow-up, but does not report the event count, median follow-up, or comparative effect interval needed to fully judge the precision of the primary contrast.

The record also illustrates the difference between a sponsor-reported analysis and an unadjusted recalculation. The primary conclusion should follow the reported log-rank analysis, while the secondary recalculations remain exploratory. Planning illustrations based on observed differences are not evidence of observed power and are not the study’s original design justification. Keeping these categories distinct prevents descriptive calculations from being mistaken for confirmatory trial results.

Finally, the multiple secondary endpoints, differing analysis populations, and unreported multiplicity and missing-data methods highlight the importance of a complete analysis plan. The registry offers useful outcome summaries, but several design and analysis details needed for a fuller evaluation are not reported. This makes careful separation of what the record shows from what remains uncertain central to statistical interpretation.

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 provides the primary medians and their confidence intervals, plus a log-rank p-value, but no hazard ratio or confidence interval for the primary between-group effect. The event count and median follow-up are not reported. Consequently, the comparative effect’s magnitude and precision cannot be characterized as fully as they could be with those statistics.

The primary analysis pools two arms under each induction category, while the arms differ in their planned maintenance treatment. The record does not report whether this pooling was prespecified, whether treatment interactions were assessed, or whether the analysis was stratified. This limits interpretation of the pooled result as a comparison of all four treatment sequences.

Several details needed to evaluate trial conduct and analysis are not reported in the registry record: the randomization method, stratification factors, full statistical plan, original sample-size justification, interim analyses, stopping rules, multiplicity procedures, censoring rules, and missing-data methods. The record also does not specify the intention-to-treat status of the primary analysis or how protocol deviations were handled.

For secondary outcomes, numerical results are not available in the record for every listed endpoint, and no sponsor-reported analyses are posted for the overall-survival result detailed. The available unadjusted recalculations are based on summary statistics and should not be treated as substitutes for a prespecified analysis. Safety counts are descriptive; information on attribution, exposure duration, event grading, and formal between-group testing is not reported.

Some arm descriptions are truncated in the registry record. Although the broad induction and maintenance assignments are identified, the available text does not support a complete reconstruction of every regimen detail. These limitations constrain interpretation of both efficacy and safety and should be kept distinct from the results that are explicitly reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Rituximab, Bendamustine Hydrochloride, and Bortezomib Followed by Rituximab and Lenalidomide in Treating Older Patients With Previously Untreated Mantle Cell Lymphoma — NCT01415752.
• Registry record last updated 2026-06-03; status last verified 2026-05.
• Results first posted 2025-04-08.
• 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

NCT01415752 is a randomized, open-label, parallel phase 2 study sponsored by the Eastern Cooperative Oncology Group. It enrolled 373 participants and concerns previously untreated mantle cell lymphoma in older patients. Four treatment arms combine RB or RBV induction with either rituximab or lenalidomide plus rituximab maintenance.

The primary endpoint is PFS among eligible and treated patients at Step 1. The posted medians are 5.5 years for RB and 6.4 years for RBV; the reported log-rank p-value is 0.25. The record does not report a primary comparative hazard ratio or its confidence interval.

Secondary outcomes include response, PET-documented complete response, and overall survival. Some secondary overall-survival comparisons are available as unadjusted recalculations, while sponsor-reported secondary analyses are not posted. Safety counts are descriptive. Details about multiplicity, missing data, censoring, and the full statistical plan are not reported in the registry record.