Pelabresib plus ruxolitinib for JAK inhibitor-naive myelofibrosis: a randomized phase 3 trial.
Rampal RK, Grosicki S, Chraniuk D, Abruzzese E, Bose P, Gerds AT, Vannucchi AM, Palandri F, Lee SE, Gupta V, Lucchesi A, Oh ST, Kuykendall AT, Patriarca A, Álvarez-Larrán A, Mesa R, Kiladjian JJ, Talpaz M, Scandura JM, Lavie D, Harris M, Kays SK, Li Q, Boxhammer R, Brown B, Jegg AM, Harrison CN, Mascarenhas J
- DOI
- 10.1038/s41591-025-03572-3
- Record issued
- 2026-08-15
- Engine
- 7.39.0
- Exported
- 2026-09-20
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/7d528e42-f4bc-4bab-98e6-070195691196 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×2−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary efficacy claim is based on spleen volume reduction (≥35% at week 24), which is a surrogate marker for clinical benefit in myelofibrosis. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data linking pelabresib exposure to BET inhibition) nor does it cite validated evidence linking spleen volume reduction to hard clinical outcomes such as survival or quality of life. Although the discussion mentions correlation with overall survival, it is not validated in this study.
“Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24.”
- 02Treatment effect not shown to be clinically meaningful
The primary effect size is a 30.4% absolute difference in spleen response rate (65.9% vs 35.2%). While statistically significant, the clinical meaningfulness is not anchored to a minimal clinically important difference or a validated threshold for spleen volume reduction. The symptom endpoint (TSS) showed a non-significant difference (-1.94, P=0.0545), and the effect on survival or other hard outcomes is not reported. The magnitude of spleen volume reduction is a surrogate and its clinical benefit is not established.
“difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001”
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 rigorously designed and transparently reported phase 3 randomized controlled trial. The manuscript demonstrates strong scientific premise, robust methodology, and comprehensive reporting across all eight rigor dimensions. Only minor copyedit issues and a few reporting refinements are noted.
Both reviewers independently scored all eight dimensions as 'pass' with high confidence, and their evidence was consistent. The study type is interventional (phase 3 RCT). Non-applicable sub-criteria (e.g., animal housing, cell line authentication) were excluded. The statistics verification covered only a subset of tests (1 recomputed consistently); the full statistical analysis was not independently re-analyzed.
Numerical inconsistencies
1 finding · worst lowValues 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.
- Internal contradictions in the reported numbersAssessed
Recomputed 1 test: 1 consistent, 0 inconsistent; 1 via agent-written checks.
- CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2Primary endpoint spleen response rate comparison using Cochran-Mantel-Haenszel test
“65.9% of patients randomized to pelabresib–ruxolitinib ( n = 214) versus 35.2% to placebo–ruxolitinib ( n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001)”
Taken as given: The percentages are applied to the randomized Ns (214 and 216) to derive event counts.; The test is a two-sided Cochran-Mantel-Haenszel test, approximated here by a chi-square test for 2x2 table.; The event counts are rounded to the nearest integer.Method: Recomputed using pChi2x2 with cell counts derived from percentages and Ns.How we recomputed it: pChi2x2(141, 73, 76, 140)
- lowinternal contradictionThe text states 'two patients in each arm had not received study treatment' but the safety population Ns are 212 and 214, which is consistent with 214-2=212 and 216-2=214. No contradiction.
“At the data cutoff (31 August 2023), two patients in each arm had not received study treatment”
ResultsFind in source - lowinternal contradictionThe abstract reports '95 CI' instead of '95% CI' for the TSS50 difference, which is a typographical inconsistency but not a validity threat.
“TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5)”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions 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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
7 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The combination improves signs of underlying myelofibrosis pathobiology.Exploratory analyses show improvements in cytokines and bone marrow morphology, but these are exploratory and not confirmatory.Evidence: Exploratory analyses of proinflammatory cytokines and bone marrow morphology showed greater improvement with the combination.
“Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination.”
AbstractFind in source - partialReviewer 2Pelabresib plus ruxolitinib improves symptoms (TSS) compared to placebo plus ruxolitinib.The key secondary endpoint of absolute change in TSS showed a trend but did not reach statistical significance (P=0.0545). TSS50 response was numerically higher but not formally tested due to hierarchical testing.Evidence: Absolute change in TSS: -15.99 vs -14.05, difference -1.94, 95% CI -3.92 to 0.04, P=0.0545. TSS50: 52.3% vs 46.3%, difference 6.0%, 95% CI -3.5 to 15.5.
“Absolute change in TSS was −15.99 versus −14.05 (difference, −1.94; 95% CI, −3.92, 0.04; P = 0.0545) and TSS50 was achieved in 52.3% versus 46.3% (difference, 6.0%; 95 CI, −3.5, 15.5)”
AbstractFind in source - supportedReviewer 1Pelabresib plus ruxolitinib resulted in a significantly higher spleen volume reduction from baseline versus placebo with ruxolitinib.The primary endpoint was met with a statistically significant difference and the effect size is plausible.Evidence: Primary endpoint result: 65.9% vs 35.2%, difference 30.4%, 95% CI 21.6-39.3, P<0.001.
“The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib ( n = 214) versus 35.2% to placebo–ruxolitinib ( n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001).”
AbstractFind in source - supportedReviewers 1, 2Pelabresib in combination with ruxolitinib is well tolerated.Safety data show manageable adverse events with no new safety signals, supporting tolerability.Evidence: Safety results: TEAEs in 96.7% both arms, grade ≥3 lower in combination arm (49.1% vs 57.0%), thrombocytopenia and anemia most common but manageable.
“Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy.”
AbstractFind in source - supportedReviewer 1The combination provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy.Primary endpoint met and secondary endpoints trend favorably, supporting clinical benefit.Evidence: Primary endpoint met; secondary endpoints showed trends (TSS change P=0.0545, TSS50 52.3% vs 46.3%).
“Pelabresib in combination with ruxolitinib is well tolerated, improves signs of underlying myelofibrosis pathobiology and provides substantial clinical benefit over standard-of-care JAK inhibitor monotherapy.”
AbstractFind in source - supportedReviewer 2Pelabresib plus ruxolitinib significantly improves spleen volume reduction compared to placebo plus ruxolitinib.The primary endpoint was met with a statistically significant difference and the effect size is large.Evidence: Primary endpoint: 65.9% vs 35.2%, difference 30.4%, 95% CI 21.6-39.3, P<0.001.
The primary endpoint was met in 65.9% of patients randomized to pelabresib–ruxolitinib (n = 214) versus 35.2% to placebo–ruxolitinib (n = 216) (difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001).
Abstractreviewer’s wording - supportedReviewer 2Pelabresib plus ruxolitinib improves underlying disease pathobiology (cytokines, bone marrow morphology).Exploratory analyses show greater improvements in cytokines and bone marrow morphology, though these are descriptive and not formally tested.Evidence: Exploratory analyses of proinflammatory cytokines and bone marrow morphology showed greater improvement with the combination.
“Exploratory analyses of proinflammatory cytokine amounts and bone marrow morphology showed greater improvement with the combination.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary efficacy claim is based on spleen volume reduction (≥35% at week 24), which is a surrogate marker for clinical benefit in myelofibrosis. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data linking pelabresib exposure to BET inhibition) nor does it cite validated evidence linking spleen volume reduction to hard clinical outcomes such as survival or quality of life. Although the discussion mentions correlation with overall survival, it is not validated in this study.
“Primary endpoint was reduction in spleen volume of ≥35% from baseline at week 24.”
- INADEQUATEEffect sizeThe primary effect size is a 30.4% absolute difference in spleen response rate (65.9% vs 35.2%). While statistically significant, the clinical meaningfulness is not anchored to a minimal clinically important difference or a validated threshold for spleen volume reduction. The symptom endpoint (TSS) showed a non-significant difference (-1.94, P=0.0545), and the effect on survival or other hard outcomes is not reported. The magnitude of spleen volume reduction is a surrogate and its clinical benefit is not established.
“difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001”
Data authenticity concerns
None foundAn 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
None foundRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
Checked — nothing surfaced.
The introduction cites prior work on JAK inhibitor monotherapy limitations and preclinical BET inhibition studies, and references the phase 2 MANIFEST study results. The rationale linking BET and JAK inhibition to improved outcomes is logically presented. Limitations of prior research (e.g., short-term treatment effects) are acknowledged and addressed by the study design.
Randomization was centralized with stratification, blinding was double-blind, power analysis was provided, and inclusion/exclusion criteria were pre-specified. The analysis population (ITT) and missing data handling (multiple imputation) are described, satisfying outlier handling. Controls are inherent in the placebo arm.
“All patients, investigators and the sponsor were blinded to treatment allocation with study drugs packaged identically.”
“All patients, investigators and the sponsor were blinded to treatment allocation with study drugs packaged identically.”
Sex, age, race, and key clinical characteristics (e.g., DIPSS, hemoglobin, platelets) are reported in Table 1. Both sexes are enrolled, so sex justification is not applicable. Age and health status are reported. Demographics are comprehensive.
“Median age (range), years | 66 (19–84) | 66 (26–88)”
The study was approved by institutional review boards/ethics committees at each site, conducted in accordance with ICH-GCP and Declaration of Helsinki, and all patients provided written informed consent. Regulatory compliance is stated.
“The study was approved by the institutional review board or independent ethics committee at each participating center and conducted in accordance with the International Council for Harmonisation E6 Guideline for Good Clinical Practice, which originates from the Declaration of Helsinki. All patients provided written informed consent.”
“The study was approved by the institutional review board or independent ethics committee at each participating center and conducted in accordance with the International Council for Harmonisation E6 Guideline for Good Clinical Practice, which originates from the Declaration of Helsinki. All patients provided written informed consent.”
Pelabresib and ruxolitinib are named with dosing regimens and manufacturer (Constellation Pharmaceuticals, a Novartis Company). Statistical software (SAS v.9.4) is identified. Other bench resources are not applicable.
“Pelabresib or matching placebo was administered orally at a starting dose of 125 mg orally once daily for 14 consecutive days, followed by a 7-day break (21-day cycle).”
“SAS v.9.4 was used to assess the impact of missing data.”
“SAS v.9.4 was used to assess the impact of missing data.”
Tests are named (Cochran–Mantel–Haenszel, ANCOVA, mixed models). Exact p-values are reported for primary and key secondary endpoints. Effect sizes with 95% CIs are provided. Software is identified. Data presentation includes per-group n and appropriate figures. Mathematical plausibility checks did not reveal errors.
“difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001”
“The exact P value is 1.64 × 10 −10 .”
“difference, 30.4%; 95% confidence interval (CI), 21.6, 39.3; P < 0.001”
The data availability statement provides a concrete route via ClinicalStudyDataRequest, a managed-access platform. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/ .”
The trial is registered (NCT04603495). CONSORT 2010 checklist is mentioned. Limitations are discussed. Conclusions are proportional. Funding and competing interests are disclosed.
“ClinicalTrials.gov identifier: NCT04603495”
“Supplementary Figs. 1 and 2 and Tables 1–3; CONSORT 2010 checklist.”
“one limitation of this study is that we have not yet reported long-term durability of response data.”
“ClinicalTrials.gov identifier: NCT04603495”
“Supplementary Figs. 1 and 2 and Tables 1–3; CONSORT 2010 checklist.”
“one limitation of this study is that we have not yet reported long-term durability of response data.”
Registered (2 IDs: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
None foundReferences 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 30 references by DOI: 29 verified — 1 no DOI (shown, not verified).
- NO DOIJAK inhibitors in the treatment of myelofibrosisNo 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.
- datahttps://www.clinicalstudydatarequest.com/UNVERIFIEDLiveness indeterminate — content not checked.
Copyediting
4 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 4 minor suggestions below.
4 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORtypoResults, Bone marrow morphology“patiients”→ patientsTypographical error in the word 'patients'.
- MINORconsistencyAbstract“95 CI”→ 95% CIMissing percentage sign in confidence interval notation.
- MINORconsistencyResults, Efficacy: patient-reported outcomes“Cochran–Mantel–Haenszel difference, 6.0%; 95% CI, −3.5, 15.5”→ Consider adding P value if available.P value not reported for TSS50 comparison.
- MINORclarityMethods, Statistical analysis“SAS v.9.4 was used to assess the impact of missing data.”→ Clarify how SAS was used for missing data (e.g., multiple imputation).Ambiguous phrasing.
The published work is robust and well-reported. An informed reader should weigh the minor reporting gaps (e.g., missing exact p-values for some secondary endpoints, ambiguous missing-data description) and the limited independent statistical verification. No erratum or re-analysis is warranted based on the current evidence.
- 1.MEDIUMreportingIn the Results section (Efficacy: patient-reported outcomes), report the exact p-value for the TSS50 comparison (currently only the CI is given).Providing exact p-values for all key secondary endpoints improves transparency and allows readers to assess statistical significance precisely.
- 2.MEDIUMreportingIn the Abstract, report the exact p-value for the key secondary endpoint of absolute change in TSS (currently reported as P = 0.0545) or clarify that it is not significant.Including the exact p-value for a key secondary endpoint in the abstract ensures completeness and avoids ambiguity about its significance.
- 3.MEDIUMstatisticsIn the Methods (Statistical analysis), clarify how SAS v.9.4 was used for missing data (e.g., specify the multiple imputation model and variables).The current phrasing is ambiguous; a detailed description of the imputation model would enhance reproducibility and reader confidence.
- 4.MEDIUMreportingIn the Results or CONSORT flow diagram, report the number of patients with missing data for the primary endpoint analysis.Quantifying missing data for the primary endpoint is essential for assessing the robustness of the imputation approach.
- 5.MEDIUMdata codeIn the Data Availability section, add a statement about the availability of the statistical analysis plan or protocol amendments.Providing access to the SAP and protocol amendments increases transparency and allows independent verification of the analysis.
- 6.LOWreportingIn the Results section, report the exact p-value for the TSS50 comparison (currently only CI is given).Consistency in reporting exact p-values across all endpoints is a good practice for transparency.
- 7.LOWreportingIn Table 1, clarify the handling of the 'not reported' race category (e.g., specify how many patients were in that category).Clarifying the 'not reported' category avoids ambiguity about the completeness of demographic data.
- 8.LOWreportingIn the Results, report the number of patients who crossed over from placebo to pelabresib (if any).Reporting crossover information is important for interpreting the intention-to-treat analysis and potential confounding.
- 9.LOWstatisticsIn the Methods or Results, add a sensitivity analysis for the primary endpoint using a different missing data handling approach.Sensitivity analyses strengthen the robustness of the primary endpoint conclusion.
- 10.LOWcopyeditIn the Results (Bone marrow morphology), correct the typo 'patiients' to 'patients'.Fixing typographical errors improves the professional quality of the manuscript.
- 11.LOWcopyeditIn the Abstract, change '95 CI' to '95% CI' for consistency.Correcting the missing percentage sign ensures clarity and consistency in notation.
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.”
- 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.
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.