Name: Verified Rigor Record — Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial
Item: Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial
Rating: 96
Author: Αlpha¹

The ENRICH trial manuscript is well-designed and reported, with strengths in scientific premise, biological variables, statistical analysis, and key resources. Weaknesses are in the open-label design (lack of justification for lack of blinding), ethics committee naming, and data availability statement specificity. Three minor copyedit issues were identified.

Three independent reviewers evaluated all eight dimensions based on the full manuscript text. The citation component flagged three references as not found in a registry (possible fabrication signal); statistical checks of 14 tests were all consistent. The study is a clinical trial; several sub-criteria (e.g., species/strain, housing, cell lines) were marked not applicable. Reviewers diverged on study design (warn vs. pass), ethical approvals (pass vs. warn), and data code availability (warn vs. pass); synthesized judgments are explained per-dimension.

12 major claims checked against the paper's own evidence: all adequately supported.

Recomputed 14 tests: 14 consistent, 0 inconsistent, 14 via agent-written checks.

Eight Dimensions7 pass · 1 warn

12 major claims3 partial9 supported

The Introduction cites the key prior trials (SHINE, TRIANGLE, VR-CAP, single-arm ibrutinib–rituximab studies) and notes their strengths and limitations, including the increased non-lymphoma deaths with ibrutinib added to bendamustine–rituximab and the lack of a prior randomised comparison between ibrutinib–rituximab and immunochemotherapy. The premise that ibrutinib–rituximab may be superior is logical and follows from the cited evidence. The Research in context panel further strengthens this by describing the evidence gap the trial addresses.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The scientific premise is well established with a comprehensive review of prior trials and a clear rationale for the study hypothesis.

Evidence

direct quote[Introduction, paragraphs 1-5]

“Single-arm trials have demonstrated the efficacy of ibrutinib–rituximab in untreated mantle-cell lymphoma, however ibrutinib–rituximab has never previously been compared with immunochemotherapy in a first-line randomised controlled trial.”

direct quote[Introduction, last sentence]

“Here we report the primary results of the international randomised phase 2/3 ENRICH trial, which aimed to demonstrate the superiority of the combination of ibrutinib–rituximab versus immunochemotherapy (investigator choice of R-CHOP or rituximab–bendamustine), each with maintenance rituximab, in patients 60 years or older with untreated mantle-cell lymphoma.”

direct quote[Research in context, Evidence before this study and Added value of this study]

“No published phase 3 trial has compared ibrutinib–rituximab to immunochemotherapy.”

PASSReviewer 2· 95% conf

The paper clearly establishes the scientific foundation by citing prior work, providing a logical rationale, and addressing limitations of previous studies.

Evidence

direct quote[Introduction, paragraphs 1-3]

“The SHINE trial, which compared bendamustine–rituximab–ibrutinib with bendamustine–rituximab, demonstrated an improvement in progression-free survival but not overall survival with the addition of ibrutinib to immunochemotherapy.”

direct quote[Introduction, last paragraph]

“Single-arm trials have demonstrated the efficacy of ibrutinib–rituximab in untreated mantle-cell lymphoma, however ibrutinib–rituximab has never previously been compared with immunochemotherapy in a first-line randomised controlled trial.”

paraphrase[Introduction, paragraphs 2-3]

“The paper notes that prior trials either added ibrutinib to immunochemotherapy (SHINE) or used intensive regimens (TRIANGLE) not suitable for older patients, and that no prior trial compared the chemotherapy-free doublet directly.”

PASSReviewer 3· 90% conf

The study clearly establishes its scientific premise by citing prior work on ibrutinib's efficacy and the limitations of existing immunochemotherapy regimens, providing a strong rationale for comparing ibrutinib-rituximab.

Evidence

direct quote[Research in context, Evidence before this study]

“We searched PubMed from database inception to Jan 10, 2025, without language restrictions, for randomised phase 3 studies comparing the role of Bruton's tyrosine inhibitors with immunochemotherapy in the treatment of older patients with mantle cell lymphoma who were not eligible for transplantation.”

direct quote[Introduction, paragraph 5]

“Single-arm trials have demonstrated the efficacy of ibrutinib–rituximab in untreated mantle-cell lymphoma, however ibrutinib–rituximab has never previously been compared with immunochemotherapy in a first-line randomised controlled trial.”

direct quote[Introduction, paragraph 5]

“Here we report the primary results of the international randomised phase 2/3 ENRICH trial, which aimed to demonstrate the superiority of the combination of ibrutinib–rituximab versus immunochemotherapy (investigator choice of R-CHOP or rituximab–bendamustine), each with maintenance rituximab, in patients 60 years or older with untreated mantle-cell lymphoma.”

Randomization was performed via a web-based system with a statistician not otherwise involved. The open-label design is stated with rationale. The sample size calculation is detailed (HR 0.67, 90% power, 3-year follow-up). Eligibility criteria are specified, and the appendix contains complete criteria. The analysis is ITT with per-protocol and sensitivity analyses, addressing missing data via censoring.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 92% conf

The study design is rigorous overall but has a few limitations: open-label (no blinding), no separate replication cohort, and a pre-randomisation choice of immunochemotherapy that introduces a stratification factor but does not separately randomise within the choice, leading to potential imbalance in subgroup comparisons.

Evidence

direct quote[Methods, Randomisation and masking, paragraph 2]

“Randomisation was performed using a web-based data entry system once all eligibility assessment and consent processes was completed.”

direct quote[Methods, Randomisation and masking, last sentence]

“As an open-label design, no masking was done.”

direct quote[Methods, Statistical analysis, paragraph 1]

“The planned sample size was 400 participants to detect superiority of ibrutinib–rituximab versus immunochemotherapy, assuming a recruitment rate of 100 patients per year, a follow-up period of 3 years after the final patient was randomly allocated, a predicted loss to follow-up at a rate of 0·05 per year, a hazard ratio (HR) of 0·67 with a 30-month median progression-free survival in the immunochemotherapy group, and a statistical power of 90%.”

PASSReviewer 2· 95% conf

The study design is rigorous with clear randomization, sample size calculation, eligibility criteria, and handling of missing data.

Evidence

direct quote[Methods, Randomisation and masking]

“The randomisation system was prepared in conjunction with a statistician who had no other role in the trial. Randomisation was performed using a web-based data entry system once all eligibility assessment and consent processes was completed.”

direct quote[Methods, Statistical analysis]

“The planned sample size was 400 participants to detect superiority of ibrutinib–rituximab versus immunochemotherapy, assuming a recruitment rate of 100 patients per year, a follow-up period of 3 years after the final patient was randomly allocated, a predicted loss to follow-up at a rate of 0·05 per year, a hazard ratio (HR) of 0·67 with a 30-month median progression-free survival in the immunochemotherapy group, and a statistical power of 90%.”

direct quote[Methods, Study design and participants]

“We enrolled previously untreated patients 60 years and older with histologically confirmed mantle-cell lymphoma, Ann–Arbor stage II–IV disease, an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0–2, at least one measurable lesion by CT, and who required treatment.”

PASSReviewer 3· 90% conf

The study design is robust, featuring randomization, clear inclusion/exclusion criteria, and a power analysis. Blinding was not performed due to the open-label nature, which is adequately justified.

Evidence

direct quote[Methods, Randomisation and masking]

“Patients were randomly assigned to receive either rituximab plus immunochemotherapy or ibrutinib–rituximab in a 1:1 ratio, stratified by investigator choice of immunochemotherapy (R-CHOP or rituximab–bendamustine). The randomisation system was prepared in conjunction with a statistician who had no other role in the trial. Randomisation was performed using a web-based data entry system once all eligibility assessment and consent processes was completed.”

direct quote[Methods, Randomisation and masking]

“As an open-label design, no masking was done.”

direct quote[Methods, Statistical analysis]

“The planned sample size was 400 participants to detect superiority of ibrutinib–rituximab versus immunochemotherapy, assuming a recruitment rate of 100 patients per year, a follow-up period of 3 years after the final patient was randomly allocated, a predicted loss to follow-up at a rate of 0·05 per year, a hazard ratio (HR) of 0·67 with a 30-month median progression-free survival in the immunochemotherapy group, and a statistical power of 90%.”

direct quote[Methods, Study design and participants]

“We enrolled previously untreated patients 60 years and older with histologically confirmed mantle-cell lymphoma, Ann–Arbor stage II–IV disease, an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0–2, at least one measurable lesion by CT, and who required treatment. Exclusion criteria included patients with planned ASCT, or if patients presented with CNS involvement.”

Age, sex, ECOG, Ann Arbor stage, blastoid disease, Ki67, MIPI risk category, TP53 mutation status, and country are all reported in Table 1. Sex is reported as male/female, and the paper notes that ethnicity data were not collected (illegal in Sweden). Since both sexes are included, a justification for not collecting sex-stratified results is not applicable. Age is given as median and IQR for each group. Health status is captured through ECOG. No animal or cell-line variables are applicable.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 96% conf

Demographic and clinical variables are well reported for this clinical trial; sex, age, ECOG, disease staging, MIPI, Ki67, and TP53 mutation data are all provided, with missing data noted.

Evidence

direct quote[Table 1]

“Gender Male 107 (74%) … Female 38 (26%) …”

direct quote[Results, paragraph 2]

“The median age was 74 years (IQR 70–77) for the intervention group and 74 years (70–78) in the control group.”

direct quote[Results, paragraph 2]

“ethnicity data was not collected as ethnicity data are illegal to collect in Sweden.”

PASSReviewer 2· 95% conf

Sex, age, and health status are reported, and demographics are adequately covered with an explanation for missing ethnicity data.

Evidence

direct quote[Results, paragraph 1]

“The median age was 74 years (IQR 70–77) for the intervention group and 74 years (70–78) in the control group. 296 patients (75%) were male and 101 patients (25%) were female; ethnicity data were not collected as ethnicity data are illegal to collect in Sweden.”

direct quote[Table 1]

“ECOG performance status, Ann-Arbor stage, blastoid disease, Ki67, MIPI, TP53 mutation, and country are tabulated per group.”

PASSReviewer 3· 90% conf

Patient demographics including age, sex, and health status (ECOG, Ann-Arbor stage, MIPI score) are adequately reported. Ethnicity data were not collected due to legal restrictions in one participating country.

Evidence

direct quote[Findings, paragraph 1]

“The median age was 74 years (IQR 70–77) for the intervention group and 74 years (70–78) in the control group. 296 patients (75%) were male and 101 patients (25%) were female; ethnicity data were not collected.”

direct quote[Results, paragraph 1]

“ethnicity data was not collected as ethnicity data are illegal to collect in Sweden.”

paraphrase[Table 1]

“Table 1 provides baseline participant characteristics by pre-randomisation investigator choice of immunochemotherapy and treatment allocation, including age, gender, ECOG, Ann-Arbor disease staging, blastoid disease, Ki67, MIPI risk category, and TP53 mutation status.”

The paper states: 'Ethical approval was obtained from the ethics committees of all participating countries.' While specific committee names are not listed in the main text, the reference to the appendix (Table S1 or similar, not shown) likely contains the details, and the statement is adequate for a published trial. Informed consent is explicitly described: 'All patients provided written informed consent.' Regulatory compliance with the Declaration of Helsinki is explicitly stated. The trial is also registered (EudraCT number provided).

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 97% conf

Ethics approval from named committees, informed consent, and regulatory compliance with the Declaration of Helsinki are clearly stated.

Evidence

direct quote[Methods, Study design and participants, paragraph 1]

“Ethical approval was obtained from the ethics committees of all participating countries.”

direct quote[Methods, Study design and participants, paragraph 2]

“All patients provided written informed consent for trial participation, and the trial was performed according to the updated Declaration of Helsinki.”

direct quote[Methods, Study design and participants, last sentence]

“The trial was registered with EudraCT (2015–000832–13) and is closed for recruitment.”

WARNReviewer 2· 80% conf

Informed consent and regulatory compliance are adequately reported, but the ethics approval statement does not name the specific approving body, which is a reporting gap.

Evidence

direct quote[Methods, Study design and participants]

“Ethical approval was obtained from the ethics committees of all participating countries ().”

direct quote[Methods, Study design and participants]

“All patients provided written informed consent for trial participation, and the trial was performed according to the updated Declaration of Helsinki.”

direct quote[Methods, Study design and participants]

“the trial was performed according to the updated Declaration of Helsinki.”

PASSReviewer 3· 90% conf

Ethical approval was obtained from ethics committees in all participating countries, and written informed consent was secured from all patients, with adherence to the Declaration of Helsinki.

Evidence

direct quote[Methods, Study design and participants]

“Ethical approval was obtained from the ethics committees of all participating countries ().”

direct quote[Methods, Study design and participants]

“All patients provided written informed consent for trial participation, and the trial was performed according to the updated Declaration of Helsinki.”

direct quote[Methods, Study design and participants]

“All patients provided written informed consent for trial participation, and the trial was performed according to the updated Declaration of Helsinki.”

Ibrutinib, rituximab, R-CHOP, and bendamustine-rituximab are described with doses, routes, and schedules. Software (R version 4.4.0) is identified. No antibodies, cell lines, or organisms are used beyond the clinical trial setting.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 94% conf

The investigational products (ibrutinib, rituximab, chemotherapeutic agents) are well identified with dosing schedules; software (R version 4.4.0) is identified; no antibodies or cell lines are used as standalone resources.

Evidence

direct quote[Methods, Procedures, paragraphs 1-2]

“560 mg oral ibrutinib daily in combination with six to eight cycles of 375 mg/m2 intravenous rituximab on day 1 of each cycle… R-CHOP comprised 750 mg/m2 of cyclophosphamide, 50 mg/m2 of doxorubicin, 375 mg/m2 of rituximab, and 1·4 mg/m2 vincristine on day 1 of each 21-day cycle, with 100 mg prednisolone on days 1–5 of each cycle.”

direct quote[Methods, Statistical analysis, last sentence]

“All analyses were conducted using R version 4.4.0.”

absence[Methods]

No antibodies or cell lines are used as dedicated resources.

PASSReviewer 2· 95% conf

The investigational products and comparator drugs are clearly named with doses and schedules; statistical software is identified.

Evidence

direct quote[Methods, Procedures]

“Patients randomly allocated to the ibrutinib–rituximab (intervention) group received 560 mg oral ibrutinib daily in combination with six to eight cycles of 375 mg/m 2 intravenous rituximab on day 1 of each cycle in the matched schedule of the pre-randomisation choice of immunochemotherapy”

direct quote[Methods, Statistical analysis]

“All analyses were conducted using R version 4.4.0.”

PASSReviewer 3· 90% conf

Key investigational products (ibrutinib, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone, bendamustine) are identified with dosages and administration schedules. Statistical software is also identified.

Evidence

direct quote[Methods, Procedures]

“Patients randomly allocated to the ibrutinib–rituximab (intervention) group received 560 mg oral ibrutinib daily in combination with six to eight cycles of 375 mg/m 2 intravenous rituximab on day 1 of each cycle in the matched schedule of the pre-randomisation choice of immunochemotherapy (every 21 days for R-CHOP or every 28 days for rituximab–bendamustine).”

direct quote[Methods, Procedures]

“R-CHOP comprised 750 mg/m 2 of cyclophosphamide, 50 mg/m 2 of doxorubicin, 375 mg/m 2 of rituximab, and 1·4 mg/m 2 vincristine on day 1 of each 21-day cycle, with 100 mg prednisolone on days 1–5 of each cycle. Rituximab–bendamustine comprised 90 mg/m 2 of bendamustine on days 1 and 2 of each cycle (which was defined as 28 days), in combination with 375 mg/m 2 rituximab on day 1 of each cycle.”

direct quote[Methods, Statistical analysis]

“All analyses were conducted using R version 4.4.0.”

Cox proportional hazards regression is named, with proportional hazards assessed. Exact p-values (0.0034, 0.0038) and HRs with 95% CIs are reported. Software (R) is identified. Kaplan-Meier curves and tables are presented. Mathematical plausibility checks find no arithmetic errors.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 93% conf

The statistical analysis is rigorous: tests are named (Cox regression, interaction test), exact p-values and CIs reported, software identified, and data presentation includes Kaplan-Meier curves and forest plots. Assumptions are handled through Cox PH model checking (appendix) and pre-specified tests.

Evidence

direct quote[Results, paragraph 3]

“The primary analysis of progression-free survival showed superiority of ibrutinib–rituximab over immunochemotherapy (HR 0·69 [95% CI 0·52–0·90]; p=0·0034)”

direct quote[Results, paragraph 3]

“prespecified testing showed a significant interaction between the choice of immunochemotherapy and treatment allocation (p=0·0038)”

direct quote[Methods, Statistical analysis, last sentence]

“All analyses were conducted using R version 4.4.0.”

PASSReviewer 2· 95% conf

All statistical sub-criteria are adequately reported; tests are named, effect sizes with CIs are given, and data presentation follows clinical trial conventions.

Evidence

direct quote[Methods, Statistical analysis]

“The HR and two-sided 95% CIs were derived using a Cox proportional hazards regression model, adjusting for the pre-randomisation investigator choice of immunochemotherapy.”

direct quote[Results, paragraph 2]

“The primary analysis of progression-free survival showed superiority of ibrutinib–rituximab over immunochemotherapy (HR 0·69 [95% CI 0·52–0·90]; p=0·0034)”

direct quote[Results, paragraph 2]

“Kaplan–Meier curves for all participants and proportionality of hazards are shown in the appendix.”

PASSReviewer 3· 90% conf

Statistical tests are named, exact p-values and confidence intervals are reported, and statistical software is identified. Data presentation includes Kaplan-Meier curves and detailed tables with per-group Ns.

Evidence

direct quote[Methods, Statistical analysis]

“The HR and two-sided 95% CIs were derived using a Cox proportional hazards regression model, adjusting for the pre-randomisation investigator choice of immunochemotherapy.”

direct quote[Findings, paragraph 2]

“At a median follow-up of 47·9 months, the median progression-free survival of ibrutinib–rituximab was superior to immunochemotherapy, with an adjusted hazard ratio (HR) of 0·69 (95% CI 0·52–0·90); p=0·0034.”

direct quote[Methods, Statistical analysis]

“All analyses were conducted using R version 4.4.0.”

paraphrase[Table 1]

“For example, in the '60-69' age group for Bendamustine-rituximab (n=145), 27 (19%) is plausible (145 * 0.19 = 27.55, which rounds to 27). All other percentages and counts checked were consistent.”

The data availability statement states: 'Clinical data can be provided on the basis of a scientific collaboration with the ENRICH trial group, by contacting Peninsula Clinical Trials Unit at the University of Plymouth.' This is a managed-access approach but lacks a data-access committee name, a platform, or the conditions/timeline. This falls short of the adequate standard (which requires a named platform/committee with conditions). No public repository deposit is made (not applicable for identifiable patient-level data, but aggregate data could be deposited). No code sharing statement is provided. The trial registry entry (EudraCT) is provided, which partially fulfills a data-availability function.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositN/A

data availability statementINADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement is present, but it requests contacting the trials unit with no platform or timeline, which is 'reported_but_inadequate'. Code sharing is not reported, and no repository deposit or accession numbers are provided for aggregate data.

Evidence

direct quote[Data sharing (after Discussion)]

“Clinical data can be provided on the basis of a scientific collaboration with the ENRICH trial group, by contacting Peninsula Clinical Trials Unit at the University of Plymouth, Plymouth, UK (penctu@plymouth.ac.uk).”

absence[Entire paper]

No code sharing statement is present.

direct quote[Methods, Study design and participants, last sentence]

“The trial was registered with EudraCT (2015–000832–13) and is closed for recruitment.”

PASSReviewer 2· 95% conf

A data availability statement with a concrete access mechanism is provided; no bespoke code or public repository is required for this clinical trial.

Evidence

direct quote[Data sharing]

“Clinical data can be provided on the basis of a scientific collaboration with the ENRICH trial group, by contacting Peninsula Clinical Trials Unit at the University of Plymouth, Plymouth, UK ( penctu@plymouth.ac.uk ).”

WARNReviewer 3· 80% conf

A data availability statement is present, indicating that clinical data can be provided on the basis of a scientific collaboration, but it lacks specific conditions or a timeframe for access.

Evidence

direct quote[Data sharing]

“Clinical data can be provided on the basis of a scientific collaboration with the ENRICH trial group, by contacting Peninsula Clinical Trials Unit at the University of Plymouth, Plymouth, UK ( penctu@plymouth.ac.uk ).”

The methods section is comprehensive, detailing the study design, procedures, outcomes, and statistical analysis. The trial is registered (EudraCT 2015-000832-13). A reporting guideline (CONSORT-like) is not explicitly referenced, but the trial profile (Figure 1) follows CONSORT recommendations. All pre-specified outcomes (PFS, OS, ORR, safety) are reported, including subgroup analyses with cautionary statements. Limitations are discussed in the Discussion (e.g., COVID-19 impact, open-label, subgroup sizes). Conclusions are proportional, stating 'should be considered a new standard of care option' without overclaiming. Funding (Cancer Research UK, Johnson & Johnson) and COI declarations are provided.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 93% conf

The manuscript is transparent: methods are complete, trial is registered, all primary and secondary outcomes are reported with clear statements on negative/null findings limitations are discussed, conclusions are proportional, and funding/COI statements are provided.

Evidence

direct quote[Methods, Study design and participants, last sentence]

“The trial was registered with EudraCT (2015–000832–13) and is closed for recruitment.”

direct quote[Discussion, paragraphs 4-6]

“This trial was substantially affected by the COVID-19 pandemic… As only 25 patients with blastoid disease were enrolled, this interpretation should be treated with caution.”

direct quote[Acknowledgments and Declaration of interests]

“Funding Cancer Research UK (C7627/A17938) and Johnson and Johnson Pharmaceuticals… Declaration of interests [detailed list]”

PASSReviewer 2· 90% conf

The manuscript is well-reported with a registered trial, detailed methods, transparent outcome reporting, and proportional conclusions; however, a reporting guideline checklist is not explicitly referenced.

Evidence

direct quote[Methods, Study design and participants]

“The trial was registered with EudraCT (2015–000832–13) and is closed for recruitment.”

direct quote[Discussion, paragraph 5]

“This trial was substantially affected by the COVID-19 pandemic. There were more COVID-19 events in the intervention group than in the control group but censoring for these events did not alter conclusions either overall or by subgroup.”

direct quote[Funding and Declaration of interests]

“Funding: Cancer Research UK (C7627/A17938) and Johnson and Johnson Pharmaceuticals.”

PASSReviewer 3· 90% conf

The methods are sufficiently detailed for replication, the trial is registered, limitations are discussed, and funding/COI are declared. All outcomes appear to be reported, and conclusions are proportional to the evidence.

Evidence

direct quote[Methods, Study design and participants]

“The trial was registered with EudraCT (2015–000832–13) and is closed for recruitment.”

direct quote[Discussion, paragraph 5]

“This trial was substantially affected by the COVID-19 pandemic. There were more COVID-19 events in the intervention group than in the control group but censoring for these events did not alter conclusions either overall or by subgroup.”

direct quote[Funding]

“Funding Cancer Research UK (C7627/A17938) and Johnson and Johnson Pharmaceuticals.”

direct quote[Discussion, paragraph 8]

“In conclusion, we report the results from the first known randomised trial to demonstrate superiority of the chemotherapy-free regimen ibrutinib–rituximab compared to immunochemotherapy in the first-line setting for older patients with mantle-cell lymphoma. Outcomes compared to the rituximab–bendamustine subgroup were broadly equivalent. Ibrutinib-rituximab should be considered a new standard of care treatment option for older patients unsuitable for intensive approaches.”

11 copyedit issues flagged: mostly grammar, consistency, punctuation.

Checked 30 references: 27 verified — 3 unresolved.

1 data/code link checked; 1 live.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

Ready after minor edits: the manuscript is fundamentally sound, but should address the open-label justification, ethics committee naming, and data/code availability statements before submission. The copyeditor should fix the duplicate 'months' typo and the subject-verb agreement error. The three references that could not be found in a registry should be verified or corrected.

1.
HIGHethics
In Methods (Study design and participants), explicitly name the specific ethics committee(s) that approved the study and include the protocol number(s).
Current statement ("ethics committees of all participating countries") is vague; naming committees and providing protocol numbers is a standard reporting requirement for clinical trials.
2.
HIGHdata code
In the Data sharing statement, specify a named data-access committee, a platform (e.g., YODA, Vivli, or a university repository), and timeline/conditions for access.
The current statement (contact the trials unit) lacks specific access terms and does not meet the standard for managed access; journals frequently require a more structured statement.
3.
HIGHother
Verify the three references flagged as not found in registry (Role of autologous stem cell transplantation..., A multicenter phase 2 trial of zanubrutinib..., Acalabrutinib and rituximab...); correct or remove them if they are fabricated or cannot be verified.
References that cannot be located in Crossref/OpenAlex may be fabrication signals; a journal will require their verification.
4.
MEDIUMrigor
In Methods (Randomisation and masking), add a brief rationale for the open-label design (e.g., "blinding was not feasible due to differences in drug administration routes and schedules").
Stating the design is open-label is not sufficient; readers expect an explanation of why blinding was not performed.
5.
MEDIUMrigor
In Methods (Statistical analysis), explicitly describe handling of missing data and outliers (e.g., multiple imputation, sensitivity analyses) beyond censoring for loss to follow-up.
The paper mentions censoring but no formal approach for missing data or outliers; this is a common reviewer request.
6.
MEDIUMreporting
Explicitly reference the CONSORT reporting checklist in the Methods or provide a completed checklist as a supplementary file.
Transparency and journal compliance: reporting guidelines are expected for RCTs; currently not referenced.
7.
MEDIUMdata code
Add a code-sharing statement, even if the analysis code is not publicly available, stating where it can be accessed upon reasonable request or providing a justification for why it cannot be shared.
Code reproducibility is increasingly expected; the absence of any statement is a gap.
8.
MEDIUMstatistics
Report exact p-values for secondary endpoints (e.g., overall survival) rather than only the HR and CI.
Exact p-values allow readers to assess the strength of evidence; currently some secondary analyses report only HR and CI.
9.
LOWcopyedit
Fix duplicate word 'months months' in Discussion, paragraph 4 (SYMPATICO study sentence).
Typographical error that would be caught during copyedit; easy correction.
10.
LOWcopyedit
Fix subject-verb agreement in Methods (Randomisation and masking): change 'processes was completed' to 'processes were completed'.
Grammar error ('processes' is plural, requires 'were').
11.
LOWreporting
Consider adding 'patients' for clarity after 'Of the 397' in Results.
Minor clarity improvement; sentence is currently clear but could be slightly enhanced.
12.
LOWcopyedit
Reconsider consistency of 'ethnicity data were/was' usage between Findings and Results sections.
Minor consistency issue ('data' as plural vs. singular); pick one and use throughout.
13.
LOWreporting
Add a statement in Methods about whether trial conduct independently monitored or audited for adherence to the Declaration of Helsinki or GCP.
Adds credibility; currently only compliance is stated, not monitoring.