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Kaimen Rigor review

Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin.

Curtis DJ, Patil SS, Reynolds J, Purtill D, Lewis C, Ritchie DS, Gottlieb DJ, Yeung DT, Wong E, Tey SK, Perera T, Moore J, Koldej RM, De Abreu Lourenco R, Stubbs J, Morrissey CO, Munsef N, Arenas A, Hill GR, Australasian Leukaemia and Lymphoma Group

DOI: 10.1056/NEJMoa2503189
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-22

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/f5016f5b-8b43-4ac4-b4fc-277e67c0381d is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

4 / 5

Strong — minor issues to address

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern−0.5★
StatisticsPrinted percentage does not match its own count (capped)−0.25★
ReportingData & code availability partially met−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 3 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
66.6% does not match the reported count 45/68
“≥ 50 years - n | 45 (66.6)”
Table 1Find in source

Findings by category

201ArithmeticNumerical inconsistencies 102OverreachOverstated conclusions 03AuthenticityNone found 104DisclosureReporting gaps 05AvailabilityNone found 06Copyedit6 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted and clearly reported phase 3 randomized trial with a strong scientific premise, rigorous design, and transparent reporting. The main weaknesses are the lack of a formal data availability statement and the absence of named statistical software, both of which are minor reporting gaps rather than validity threats.

Both reviewers agreed on all dimensions and the study type (interventional). The statistics verification component recomputed only one test (the primary HR) and found it inconsistent with the reported value, but this is a single check with limited coverage and does not constitute a demonstrable error in the paper's own reporting. The GRIM/GRIMMER checks are not applicable to continuous measurements. The citation check found no retracted or unresolved references.

Numerical inconsistencies

2 findings · worst medium

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

1 printed percentage that does not match its own count.

Numeric forensics— values impossible for the reported sample size

PERCENT
66.6% does not match the reported count 45/68
“≥ 50 years - n | 45 (66.6)”
Table 1Find in source

lowinternal contradiction
The text reports 54.5% for immunosuppression-free survival at 12 months in the investigational arm, but Table 3 reports 54.4%.
the proportions of patients at 12 months that were in remission and free of systemic immunosuppression (see for definition) were 30.9% (95%CI: 20.2-43.3) and 54.5% (95%CI: 41.8-66.9) in the control and investigational arms, respectively.
Table 3reviewer’s wording

Overstated conclusions

1 finding · worst low

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Conclusions only partially backed by the presented evidenceAssessed

7 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.

partialReviewers 1, 2
PTCy-cyclosporin improves relapse-free survival but not overall survival.
Relapse-free survival shows a favorable HR (0.547, 95% CI 0.299-1.001) but the confidence interval includes 1, so it is not statistically significant at the 0.05 level. Overall survival HR is 0.591 (95% CI 0.294-1.188), also not significant. The claim is partially supported as the point estimates favor PTCy but are not definitive.
Evidence: Results: RFS HR 0.547 (95% CI 0.299-1.001); OS HR 0.591 (95% CI 0.294-1.188).
“At 2 years, 74.5% of the experimental arm patients and 59.3% of control arm patients were relapse-free (estimated HR 0.547; 95% CI: 0.299-1.001)”
ResultsFind in source
supportedReviewer 1
Dual GVHD prophylaxis with PTCy plus cyclosporin significantly improved long-term GRFS without increasing toxicity in PBSCT using MRD.
The primary endpoint GRFS is significantly improved (p<0.0001, HR 0.419, 95% CI 0.267-0.656), and adverse events are not increased in the first 100 days. The claim is directly supported by the presented data.
Evidence: Primary endpoint analysis: GRFS median 26.2 vs 6.4 months, p<0.0001, HR 0.419 (95% CI 0.267-0.656). Safety data: no increase in serious adverse events.
“The combination of PTCy and a calcineurin inhibitor has a high level of activity in reducing graft-vs-host disease and preserving disease-free survival after transplantation using a MRD with either reduced-intensity or myeloablative conditioning for blood cancers.”
AbstractFind in source
supportedReviewers 1, 2
PTCy-cyclosporin reduces rates of grade III-IV acute GVHD and moderate-severe chronic GVHD.
Cumulative incidences show lower rates in the investigational arm for both acute and chronic GVHD, with confidence intervals that do not overlap at several time points.
Evidence: Table 3: Grade III-IV acute GVHD at 6 months: 17.8% vs 6.4%; moderate-severe chronic GVHD at 12 months: 23.9% vs 14.5%.
“The cumulative incidences of moderate-severe cGVHD shown in are suggestive of a difference between the treatment arms.”
Table 3Find in source
supportedReviewer 1
The improvement in GRFS is driven primarily by reductions in GVHD, not by differences in relapse or survival.
The paper shows that the cumulative incidences of relapse and non-relapse mortality are similar between arms, while GVHD rates differ, supporting the claim.
Evidence: Table 3: Relapse at 24 months: 21.1% vs 16.2%; non-relapse mortality at 24 months: 5.9% vs 6.3%. The paper states 'the difference in the primary endpoint of GRFS between the prophylaxis arms appeared to be driven primarily by differences in the incidences of grade III-IV acute and moderate-severe chronic GVHD'.
“Overall, the difference in the primary endpoint of GRFS between the prophylaxis arms appeared to be driven primarily by differences in the incidences of grade III-IV acute and moderate-severe chronic GVHD”
ResultsFind in source
supportedReviewer 2
PTCy-cyclosporin significantly improves GRFS compared to cyclosporin-methotrexate.
The primary endpoint analysis shows a significant difference with a hazard ratio of 0.419 and p<0.0001, directly supporting the claim.
Evidence: Primary endpoint analysis: median GRFS 26.2 vs 6.4 months, HR 0.419 (95% CI 0.267-0.656), p<0.0001.
“There was a significant difference in GRFS (Log-Rank test p<0.0001): median 26.2 months (95%CI:9.1-not reached) with PTCy-cyclosporin and 6.4 months (95% CI:5.6-8.3) with cyclosporin-methotrexate.”
AbstractFind in source
supportedReviewer 2
Serious adverse events were not increased with PTCy-cyclosporin in the first 100 days.
The reported adverse event rates are lower in the investigational arm, supporting the claim.
Evidence: Grade 3 or worse adverse events: 32.4% in control vs 19.7% in investigational; ICU admissions: 11 vs 9.
“In the control arm, 22 (32.4%) patients had at least one Grade 3 or worse adverse event reported including 5 (7.4%) with Grade 5 (). In the investigational arm, 12 (19.7%) had at least one grade 3 or worse event reported including 4 (6.6%) with Grade 5 ().”
ResultsFind in source
supportedReviewer 2
The combination of PTCy and a calcineurin inhibitor has a high level of activity in reducing graft-vs-host disease and preserving disease-free survival.
The primary and secondary endpoints support this conclusion, though the trial is open-label and not blinded, which is a limitation.
Evidence: Primary endpoint GRFS significantly improved; secondary endpoints show reduced GVHD and improved RFS.
“The combination of PTCy and a calcineurin inhibitor has a high level of activity in reducing graft-vs-host disease and preserving disease-free survival after transplantation using a MRD with either reduced-intensity or myeloablative conditioning for blood cancers.”
ConclusionFind in source

Efficacy claim is anchored to an adequate endpoint and a meaningful effect.

ADEQUATESurrogate endpoint
The primary endpoint is GVHD-free, relapse-free survival (GRFS), a composite of hard clinical outcomes (grade III-IV acute GVHD, moderate-severe chronic GVHD, relapse, death). These are clinical events, not surrogate biomarkers. The paper also reports overall survival and relapse-free survival as secondary endpoints. No surrogate biomarker is used as the primary basis for efficacy.
“The primary endpoint was time-to-event GRFS measured from the date of stem cell transplantation until the date of the earliest occurrence of any one of grade III or greater acute GVHD using MAGIC criteria, NIH-defined moderate or severe chronic GVHD, morphological relapse or death from any cause.”
Find in source
ADEQUATEEffect size
The primary endpoint GRFS showed a significant improvement with PTCy-cyclosporin: median GRFS 26.2 months vs 6.4 months, 3-year GRFS 49.3% vs 14.1%, HR 0.419 (95% CI 0.267-0.656), p<0.0001. This is a large and clinically meaningful difference, anchored to a composite of hard clinical outcomes. The effect size is statistically supported and clinically material.
“There was a significant difference in GRFS (Log-Rank test p<0.0001): median 26.2 months (95%CI:9.1-not reached) with PTCy-cyclosporin and 6.4 months (95% CI:5.6-8.3) with cyclosporin-methotrexate. The 3-year GRFS was 49.3% (95%CI:36.0-61.2) with PTCy-cyclosporin and 14.1% (95%CI:6.4-24.7) with cyclosporin-methotrexate. The hazard ratio was 0.419 (95%CI:0.267-0.656).”
Find in source

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

1 finding · worst medium

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Data/code availability incompleteAssessed

Eight Dimensions7 pass · 1 warn

The introduction cites multiple randomized trials (BMT CTN 1703, HOVON-96) and single-arm studies that explored PTCy, and explicitly states the knowledge gap: 'the benefit of PTCy for PBSCT using a MRD remains uncertain, and unknown in the context of myeloablative conditioning.' The rationale linking this gap to the study objectives is logical. Limitations of prior research (e.g., HOVON-96's use of non-myeloablative conditioning, small MRD subgroup) are acknowledged.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper clearly establishes the scientific premise, citing prior work on GVHD prophylaxis and the rationale for testing PTCy-cyclosporin, and acknowledges limitations of prior studies.

Evidence

paraphrase[Introduction, paragraphs 3-5]

“The BMT CTN 1703 trial assessed triple GVHD prophylaxis in recipients of PBSCs from a matched related or unrelated donor receiving reduced-intensity or non-myeloablative conditioning.”

“the benefit of PTCy for PBSCT using a MRD remains uncertain, and unknown in the context of myeloablative conditioning, which was excluded from both the BMT CTN 1703 and HOVON-96 trials.”

Introduction ¶5Find in source

“the conclusions from HOVON-96 are limited by the small number of PBSCTs using MRDs and the use of non-myeloablative conditioning”

Discussion ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise by citing prior randomized trials and identifying a specific knowledge gap.

Evidence

paraphrase[Introduction, paragraph 3]

“The BMT CTN 1703 trial assessed triple GVHD prophylaxis in recipients of PBSCs from a matched related or unrelated donor receiving reduced-intensity or non-myeloablative conditioning. Post hoc analysis of the MRD subgroup suggested benefit for GVHD-free, relapse-free survival (GRFS).”

“As a result, the benefit of PTCy for PBSCT using a MRD remains uncertain, and unknown in the context of myeloablative conditioning, which was excluded from both the BMT CTN 1703 and HOVON-96 trials.”

Introduction ¶4Find in source

“Here, we present the results of the phase 3 randomized ALLG BM12 CAST trial, which aimed to establish the benefit of the dual GVHD prophylaxis regimen (PTCy-cyclosporin) for PBSCT using a MRD in the context of either reduced-intensity or myeloablative conditioning.”

Introduction ¶4Find in source

The trial is described as 'prospective, open-label, two-arm randomized phase 3 trial.' Randomization was stratified by age and conditioning intensity. A sample size of 134 patients was selected to achieve 80% power for a two-sided log-rank test (α=0.05) to detect a hazard ratio of 0.54. Inclusion/exclusion criteria are described, and the primary endpoint (GRFS) is clearly defined. Blinding is not performed, but the open-label design is explicitly stated. For a clinical trial, the applicable sub-criteria (randomization_method, randomization_unit, blinding_levels, power_analysis, inclusion_exclusion, outlier_handling) are all adequately addressed: randomization method is stated (1:1 ratio, stratified), unit is the patient, power analysis is reported, inclusion/exclusion criteria are given, and the analysis population (ITT) and handling of non-transplanted patients are described. Blinding is not applicable as a requirement for an open-label trial when stated.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study design is rigorous: a randomized phase 3 trial with stratification, a pre-specified primary endpoint, and a sample size calculation. Blinding is absent but the open-label design is stated.

Evidence

paraphrase[Methods, Statistical Analysis]

“A total of 134 patients were randomized to the two treatment arms using a 1:1 allocation ratio... Randomization was stratified by age (dichotomised at 50 years) and intensity of the conditioning regimen (myeloablative or reduced intensity).”

paraphrase[Methods, Statistical Analysis]

“A sample size of 134 patients... was selected to achieve an 80% power for a two-sided log-rank test (a=0.05) to detect a hazard ratio of 0.54, corresponding to 86 total primary events.”

“The Australasian Leukaemia & Lymphoma Group (ALLG) BM12 CAST trial is a prospective, open-label, two-arm randomized phase 3 trial”

MethodsFind in source

PASSReviewer 2· 90% conf

The trial design is rigorous with clear randomization, stratification, and pre-specified analysis, though it is open-label.

Evidence

“A total of 134 patients were randomized to the two treatment arms using a 1:1 allocation ratio, following the decision to transplant but not more than 28 days before transplant admission to minimize dropout before PBSCT. Randomization was stratified by age (dichotomised at 50 years) and intensity of the conditioning regimen (myeloablative or reduced intensity).”

Statistical analysisFind in source

“A sample size of 134 patients, guided by results of the single arm PTCy-cyclosporin study , was selected to achieve an 80% power for a two-sided log-rank test (a=0.05) to detect a hazard ratio of 0.54, corresponding to 86 total primary events.”

Statistical analysisFind in source

“Some limitations of CAST should be noted including the non-blinded nature of the study that could bias GVHD assessments”

Discussion ¶4Find in source

Table 1 reports age (mean, median, range, proportion ≥50 years), sex (male %), CMV status, primary disease, disease risk index, comorbidity-age index, donor sex match, and donor age. Both sexes are enrolled (55.2% male), so a justification for single-sex is not required. Age, weight/health status is captured via comorbidity-age index. Species/strain/housing are not applicable for a human clinical trial. Demographics are adequately reported.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Key biological variables (age, sex, disease, CMV status) are reported in Table 1. Sex is reported and both sexes are enrolled, so sex_justified is not applicable. Demographics are adequately reported.

Evidence

“Male sex – n (%) | 37 (54.4) | 37 (56.1) | 74 (55.2)”

Table 1Find in source

paraphrase[Table 1]

“Primary disease – n (%) | Acute myeloid leukemia | 44 (64.7) | 38 (57.6) | 82 (61.2)”

PASSReviewer 2· 90% conf

Key biological variables such as age, sex, and disease characteristics are reported in baseline tables.

Evidence

“Male sex – n (%) | 37 (54.4) | 37 (56.1) | 74 (55.2)”

Table 1Find in source

“Mean, years (SD) | 52.9 (12.3) | 51.4 (14.1) | 52.2 (13.2)”

Table 1Find in source

The paper states: 'approved by the Human Research Ethics Committee at each participating site' and 'All patients provided informed consent to participate.' Regulatory compliance is implied by the trial registration (ACTRN12618000505202) and adherence to the Declaration of Helsinki is referenced in the context of the protocol. The ethics statement names the approving body (Human Research Ethics Committee) and consent is described.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethics approval from a named committee at each site, informed consent, and regulatory compliance are all reported.

Evidence

“approved by the Human Research Ethics Committee at each participating site”

MethodsFind in source

“All patients provided informed consent to participate.”

MethodsFind in source

“The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618000505202)”

MethodsFind in source

PASSReviewer 2· 95% conf

The trial has appropriate ethics approval and informed consent, with a named registry and ethics committee approval.

Evidence

“The trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12618000505202) and approved by the Human Research Ethics Committee at each participating site.”

MethodsFind in source

“All patients provided informed consent to participate.”

MethodsFind in source

The paper describes the drugs used (cyclophosphamide, cyclosporin, methotrexate) with doses and schedules. The investigational product is adequately identified. Software tools are not explicitly named (e.g., SAS, R) but the statistical methods are described; however, for a clinical trial, the key resource is the drug regimen, which is reported. Antibodies, cell lines, mycoplasma testing, and organisms are not applicable. The paper does not name the statistical software, which is a minor gap but does not affect the overall pass given the adequate reporting of the investigational product.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedINADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The investigational product (cyclophosphamide, cyclosporin, methotrexate) is identified with dosing regimens. Software tools are identified (SAS? not explicitly named but statistical methods are described). No antibodies, cell lines, or organisms are used, so those are not applicable.

Evidence

paraphrase[Methods, Trial procedures]

“The control GVHD prophylaxis consisted of methotrexate (intravenous bolus of 15 mg per meter squared on day 1 and 10 mg per meter squared on days 3, 6 and 11) and cyclosporin... The investigational GVHD prophylaxis consisted of cyclophosphamide (50 mg per kilogram on days 3 and 4 after transplant followed by cyclosporin”

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

PASSReviewer 2· 85% conf

The investigational product (PTCy and cyclosporin) and control (methotrexate and cyclosporin) are adequately identified with dosing details.

Evidence

“The control GVHD prophylaxis consisted of methotrexate (intravenous bolus of 15 mg per meter squared on day 1 and 10 mg per meter squared on days 3, 6 and 11) and cyclosporin (dosing and monitoring levels as per institutional practice) starting 1 to 3 days before transplant and tapered not before day 90.”

MethodsFind in source

absence[Methods, Statistical Analysis]

Statistical software is not explicitly named.

The primary analysis uses the log-rank test and Cox proportional hazards model, with the hazard ratio and 95% CI reported. Exact p-values are provided (p<0.0001). Effect sizes with CIs are reported for GRFS, RFS, OS, and other endpoints. Data presentation includes Kaplan-Meier curves and cumulative incidence plots. Assumptions for Cox PH are not explicitly verified but are standard for this type of analysis. The paper does not name the statistical software (e.g., SAS, R), which is a minor inadequacy. Mathematical plausibility checks: the reported percentages and counts in Table 2 sum correctly (e.g., 12+0+13+23+16+4 = 68 for control; 31+4+4+11+12+4 = 66 for investigational). The GRFS event count (87) is consistent with the sum of first events (17+34+28+8 = 87). No arithmetic errors detected.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedINADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityPASS

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical tests are named (log-rank, Cox PH), effect sizes with CIs are reported, and data presentation includes Kaplan-Meier curves and cumulative incidence. Exact p-values are given for the primary endpoint. Assumptions are handled by design (Cox PH). Software is not named, which is a minor gap.

Evidence

paraphrase[Results, Primary Endpoint]

“GRFS was significantly improved in the PTCy group with median GRFS of 26.2 months (95% CI:9.1-not reached) with PTCy-cyclosporin and 6.4 months (95% CI:5.6-8.3) in the control arm (Log-Rank test p-value <0.0001). The estimated hazard ratio (HR) was 0.419 (95% CI:0.267-0.656)”

paraphrase[Table 2]

“First Event | Control prophylaxis - n (%) | Investigational prophylaxis - n (%) | Total - n (%) | | Event-free | 12 (17.7) | 31 (47.0) | 43 (32.1) | ... | Total | 68 (50.7) | 66 (49.3) | 134 (100.00)”

PASSReviewer 2· 85% conf

Statistical methods are appropriate and well-described, with exact p-values for the primary endpoint and effect sizes with confidence intervals.

Evidence

“Estimation of a hazard ratio was based on a Cox proportional hazards (PH) regression model. Formal hypothesis testing was restricted to the unadjusted analysis of the primary endpoint (GRFS).”

Statistical analysisFind in source

paraphrase[Results, Primary Endpoint]

“The estimated hazard ratio (HR) was 0.419 (95% CI:0.267-0.656)”

ResultsFind in source

The paper states 'The full protocol is available at NEJM.org (http://NEJM.org)' but does not provide a data availability statement for the individual patient data. The trial registration number is given, but no repository deposit or accession numbers are provided. Code sharing is not mentioned. For a clinical trial, managed access is acceptable, but the paper does not describe any mechanism for data access beyond the protocol. This is a common gap but still a warn.

Sub-criteria

code sharingNOT REPORTED

accession numbersN/A

repository depositNOT REPORTED

data availability statementINADEQUATE

Per reviewer (2) — the votes behind the verdict

WARNReviewer 1· 85% conf

A data availability statement is present but vague ('available from the corresponding author on reasonable request' is implied but not explicitly stated; the paper mentions the protocol is available at NEJM.org). No repository deposit or code sharing is reported.

Evidence

“The full protocol is available at NEJM.org (http://NEJM.org)”

MethodsFind in source

absence[Entire paper]

No data repository deposit is reported.

WARNReviewer 2· 80% conf

The paper states that the protocol is available online, but does not provide a data availability statement or code sharing.

Evidence

absence[Entire paper]

No data availability statement is present.

“The full protocol is available at NEJM.org (http://NEJM.org) .”

MethodsFind in source

The trial registration number is provided. Methods are detailed enough for replication. Limitations are discussed (open-label, lack of ATG, limited adverse event collection). Conclusions are proportional to the evidence, acknowledging the open-label design and the need for further trials. Funding sources and conflict of interest disclosures are provided. A reporting guideline (CONSORT) is not explicitly referenced, but the paper's structure is consistent with it. All pre-specified outcomes appear to be reported (primary and secondary).

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The trial is registered (ACTRN12618000505202), methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are reported. No reporting guideline checklist is mentioned, but the paper follows CONSORT-like structure.

Evidence

“ALLG BM12 CAST trial number: ACTRN12618000505202”

AbstractFind in source

“Some limitations of CAST should be noted including the non-blinded nature of the study that could bias GVHD assessments and the lack of adverse events collected beyond the first 100 days after transplant”

Discussion ¶4Find in source

“The trial was funded by grants from the Australian Government Medical Research Future Fund (MRF1152188), the National Health and Medical Research Council (1135107), the Auckland Medical Research Foundation (2121002), and the Cancer Society of New Zealand (20.01).”

FundingFind in source

PASSReviewer 2· 90% conf

The paper is transparent about methods, limitations, and funding, and reports all pre-specified outcomes.

Evidence

“ALLG BM12 CAST trial number: ACTRN12618000505202.”

AbstractFind in source

Discussion ¶4Find in source

FundingFind in source

Registered (1 ID: ANZCTR). No reporting guideline cited.

ANZCTR

ACTRN12618000505202

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 35 references by DOI: 33 verified — 2 no DOI (shown, not verified).

NO DOI
GVHD Prophylaxis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

1 data/code link found; not probed for liveness in this run.

datahttp://NEJM.orgUNVERIFIEDHTTP 403
Liveness indeterminate — content not checked.

Copyediting

6 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 6 minor suggestions below.

6 copyedit issues flagged: mostly consistency, clarity, typo.

MINORconsistencyTable 1 footnote
“Control prophylaxis received cyclosporin-methotrexate and the investigational prophylaxis received post-transplant cyclophosphamide-cyclosporin.”
→ Consider adding a period at the end of the footnote or formatting as a complete sentence.
Minor formatting inconsistency.
MINORclarityResults, Other Endpoints
“The cumulative incidences for relapse and death are shown in and and did not appear to be different.”
→ Revise to 'The cumulative incidences for relapse and death are shown in [Figure/Table] and did not appear to be different.'
Missing figure/table reference.
MINORtypoResults, Other Endpoints
“The cumulative incidences for relapse and death are shown in and and did not appear to be different.”
→ Remove duplicate 'and'.
Duplicate word.
MINORconsistencyAbstract, Results
“The 3-year GRFS was 49.3% (95%CI:36.0-61.2) with PTCy-cyclosporin and 14.1% (95%CI:6.4-24.7) with cyclosporin-methotrexate.”
→ Ensure consistent use of spaces around colons in confidence intervals (e.g., '95% CI: 36.0-61.2').
Minor formatting inconsistency.
MINORclarityMethods, Trial procedures
“The only difference in conditioning between the two arms was in the TBI-based myeloablative cohort, where high-dose cyclophosphamide was replaced by fludarabine in the investigational arm due its proven efficacy with PTCy and the lack of safety data for cyclophosphamide-TBI 12Gy.”
→ Change 'due its' to 'due to its'.
Grammatical error.
MINORconsistencyTable 3
“Immunosuppression-Free Survival | 12 months | 30.9 (20.2-43.3) | 54.4 (41.8-66.9)”
→ In the text, the value is 54.5% but in the table it is 54.4%. Ensure consistency.
Minor discrepancy between text and table.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor reporting gaps (data availability, software identification) and the single inconsistent recomputation of the primary HR, which may warrant an erratum or independent re-analysis to confirm the reported effect size. No major validity threats were identified.

1.
HIGHdata code
Add a data availability statement in the Methods or a dedicated Data Sharing section specifying how de-identified patient-level data can be accessed (e.g., via a data access committee or a managed-access platform like Vivli).
The paper currently only mentions protocol availability, leaving patient-level data access unspecified, which is a common but important reporting gap for clinical trials.
2.
HIGHstatistics
Re-verify the reported primary hazard ratio (0.419, 95% CI 0.267-0.656) against the raw data or analysis code, as the independent recomputation was inconsistent.
A single inconsistent recomputation of the primary effect size warrants confirmation to ensure the headline result is accurate.
3.
MEDIUMreporting
Name the statistical software (e.g., SAS version 9.4, R version 4.x) used for analyses in the Statistical Analysis section.
Both reviewers flagged the absence of software identification as a minor inadequacy that affects reproducibility.
4.
MEDIUMreporting
Explicitly state adherence to a reporting guideline (e.g., CONSORT) and include the checklist as a supplement.
The paper follows CONSORT-like structure but does not explicitly reference the guideline, which is a transparency gap.
5.
MEDIUMdata code
Provide a statement about code availability if any custom code was used for analysis; otherwise, note that standard software was used.
Code sharing enhances reproducibility and is expected for clinical trial analyses.
6.
MEDIUMdata code
Consider depositing the study protocol and statistical analysis plan in a public repository (e.g., ClinicalTrials.gov or a registry) with a permanent identifier.
A permanent identifier for the protocol and SAP improves transparency and long-term access.
7.
MEDIUMcopyedit
Fix the duplicate 'and' and missing figure/table reference in the sentence 'The cumulative incidences for relapse and death are shown in and and did not appear to be different.' in Results, Other Endpoints.
This is a clear typographical error that obscures the intended reference.
8.
MEDIUMcopyedit
Correct the grammatical error 'due its' to 'due to its' in Methods, Trial procedures.
This is a minor grammatical error that should be fixed for clarity.
9.
MEDIUMcopyedit
Resolve the discrepancy between the text (54.5%) and Table 3 (54.4%) for immunosuppression-free survival at 12 months in the investigational arm.
Internal consistency between text and tables is essential for reader trust.
10.
LOWcopyedit
Add a period at the end of the Table 1 footnote or format it as a complete sentence.
Minor formatting inconsistency in the footnote.
11.
LOWcopyedit
Ensure consistent use of spaces around colons in confidence intervals (e.g., '95% CI: 36.0-61.2') throughout the abstract and text.
Consistent formatting improves readability and professionalism.

Full text (34,108 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Graft-versus-Host Disease Prophylaxis with Cyclophosphamide and Cyclosporin.

DOI

10.1056/NEJMoa2503189

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-22