Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation (NCT04281498), a na phase 2 study. The primary outcome is Number of MPN Participants With Response.

2. Clinical Question

The study rationale in the registry describes IDH mutations as associated with worse survival in MF and as events encountered in MPNs that have progressed to acute myeloid leukemia. It also states the study team's hypothesis that combining a JAK1/2 inhibitor with an IDH2 inhibitor might improve overall clinical response in patients with IDH2-mutated MPN. That rationale and hypothesis frame the question; they are not evidence of a treatment effect. The record also lists blast response among the secondary outcomes for MPN participants, and any response among the secondary outcomes for MF-CP participants. Those outcomes do not replace the primary question, which concerns response in the accelerated-phase and blast-phase MPN cohort.

3. Trial Design

This was a phase II, open-label study with a single-group model. The registry records no masking and allocation as not applicable. The group description specifies ruxolitinib and enasidenib combination therapy for patients with MPN; no comparator arm is recorded. Enrollment was 6, and the study status is completed. The recorded start date is 2021-01-14, and the primary completion date is 2023-05-30.

The trial included more than one disease setting: accelerated-phase or blast-phase MPN and chronic-phase MF with an IDH2 mutation. The primary outcome description narrows its response assessment to treated accelerated-phase and blast-phase MPN participants. The registry lists MF-CP participants with any response as a secondary outcome, so the enrolled population and the primary outcome cohort should not be treated as interchangeable. The record does not report how enrollment was distributed between these disease groups.

In a single-group study, the observed count describes outcomes among people who received the combination. Without a concurrent comparator, the study design does not separate treatment-associated changes from other explanations, such as the course of disease or differences among participants. Open-label status means masking is not part of the recorded design; the registry does not describe additional safeguards for response assessment.

The registry record does not report the protocol's sample-size justification, a target enrollment, recruitment details, dose schedule, or treatment duration beyond the response assessment within 6 cycles. It also does not report an interim-analysis plan or a more detailed statistical-analysis plan. Completion status indicates the recorded study is completed, but by itself does not establish that every planned assessment was reported.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Data for participants with MPN

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of MPN Participants With Response, measured over 6 Months.

The primary endpoint is the number of treated accelerated-phase and blast-phase MPN participants who achieved a best response of complete response (CR), partial response (PR), or complete response with incomplete recovery of counts (CRi), assessed within 6 cycles of combined therapy. The registry identifies the timeframe as 6 Months and cites 2013 International Working Group criteria. The endpoint is a count of participants, not a time-to-event measure or a continuous measurement.

The response categories capture different patterns of disease status. CR requires marrow and count recovery, resolution of disease symptoms, non-palpable spleen and liver, and no evidence of extramedullary hematopoiesis. CRi describes complete remission with incomplete count recovery, including platelet count <100 x 10^9/L and/or absolute neutrophil count <1 x 10^9/L. PR allows morphologic remission in peripheral blood without requiring marrow remission, alongside symptom resolution, non-palpable spleen and liver, and no evidence of extramedullary hematopoiesis.

As a general statistical concept, a prespecified categorical response endpoint can provide a clinically interpretable summary of whether participants met defined criteria during an assessment window. Its interpretation depends on consistent assessment and clear handling of participants without an evaluable response. Those procedures are not reported in the registry record. The primary response count itself is also not reported, so the endpoint definition is available but its observed result is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The recorded design is single-group and open-label, with allocation listed as not applicable and masking listed as none. These details determine what kinds of conclusions the design can support. The main efficacy outcome is a participant count meeting response criteria, while the posted safety entries are counts of affected participants and a death count. No efficacy analysis results are reported in the registry record.

What does a participant count describe?

A count states how many participants in the defined outcome population met the event definition. In this study, the event is achieving one of the response categories specified for the primary endpoint within the assessment window. A count is naturally tied to its denominator: interpretation requires knowing which participants were considered eligible for the outcome and whether all had an assessable response. The record identifies the primary cohort as treated accelerated-phase and blast-phase MPN patients, but does not report its size, the response count, or the handling of participants without an assessment.

As a general concept, a proportion expresses a count relative to a denominator, while a confidence interval describes uncertainty around an estimate under stated statistical assumptions. Neither a primary response proportion nor its confidence interval is reported in the registry record. No estimate should be inferred from enrollment alone, because enrollment includes the study population and does not establish how many belonged to the primary cohort or achieved response.

Why does the single-group design matter?

In a comparative trial, an analysis can estimate a contrast between treatment groups. Here, the registry records one treatment group receiving ruxolitinib and enasidenib. A descriptive response result, if reported, would characterize outcomes among participants in that group. It would not on its own estimate the difference that the combination caused relative to another treatment. General sources of uncertainty in uncontrolled research include the underlying course of disease, participant characteristics, and outcome assessment. The registry does not report methods to address these issues.

Open-label means that masking was not used, as reflected in the registry design. For a response endpoint requiring application of clinical criteria, knowledge of treatment assignment can be relevant to assessment in general. The registry record does not state whether response was reviewed by a blinded committee, adjudicated independently, or assessed using another procedure, so no such method can be assumed.

What is the role of a confidence interval?

In general, a confidence interval gives a range of values compatible with observed data under a specified statistical method; it communicates precision as well as the central estimate. It is not reported for the primary outcome in the registry record. Without the response count, denominator, and analysis details, there is no posted estimate whose precision can be interpreted. The absence of an interval in the registry entry should not be replaced with an interval calculated from enrollment or safety counts.

How should the sample-size illustrations be understood?

The planning illustrations are described as calculations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. They describe participants per arm for the stated power levels, with the effect set to a stated fraction of the observed effect. These are planning illustrations, not observed power and not evidence about the study's actual design. The trial is recorded as single-group, so the equal-allocation, two-arm assumption does not match its registered design. The registry does not report that these assumptions were used to plan enrollment, and it does not report the protocol's sample-size justification. Moreover, the primary efficacy result needed to understand an observed effect is not reported in the registry record.

As a general statistical concept, power calculations address the chance that a planned analysis will detect an effect of a specified size under model assumptions. They depend on assumptions about the effect, variability, design, and analysis. A planning calculation cannot be interpreted as the probability that this completed study demonstrated benefit, and it does not turn an unreported endpoint into an observed result. These illustrations should be read only as hypothetical design calculations under their stated assumptions.

Why can over-dispersion matter?

General explanation: over-dispersion occurs when observed variability in count data is greater than a model assumes. If a model ignores that extra variability, uncertainty may be understated and inferential results may be too optimistic. The registry outcome is a participant count, but no model-based efficacy analysis or dispersion estimate is reported. There is therefore no basis for asserting that over-dispersion was present or that a particular count model was used. For a small single-group count, a clear denominator and transparent descriptive reporting are especially important; the record does not provide the primary response count or its uncertainty.

Finally, the registry provides outcome definitions but little detail on analytic implementation. It does not report methods for missing observations, covariate adjustment, sensitivity analyses, or interim looks. Without those details, the methodological interpretation should remain at the level of the registered design and endpoint rather than assuming an analysis that is not documented.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Patients With MPN")
n      <- c(5)
events <- c(2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Patients With MPN  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary outcome of response among accelerated-phase and blast-phase MPN participants, as well as secondary outcomes for MPN participants with blast response and MF-CP participants with any response. Multiple outcomes can raise a multiplicity question: if several hypotheses are tested, the chance of at least one apparently notable result can increase unless the analysis plan addresses that issue. This is a general statistical concern, not evidence that the study performed multiple tests. The registry record does not report a multiplicity adjustment, a hierarchy for testing outcomes, or an inferential analysis.

The record describes outcome populations, but it does not report detailed analysis populations such as an intention-to-treat set, a treated set, or an evaluable-response set. It identifies the primary endpoint as applying to treated accelerated-phase and blast-phase MPN patients, and the population description refers to data for participants with MPN. The number in the primary cohort and the rules for inclusion in each outcome analysis are not reported in the registry record. Enrollment of 6 does not establish the denominator for any particular endpoint.

Missing-data handling is also not described. The record does not state how participants without response assessments, early treatment discontinuations, or incomplete follow-up were handled for the primary or secondary outcomes. In general, missing outcomes can affect both the denominator and interpretation of a response count; excluding participants, treating them as non-responders, or using another approach can lead to different summaries. No specific approach can be attributed to this study from the registry record.

The registry record does not report a statistical-analysis plan, interim-analysis procedures, sensitivity analyses, or other methods for addressing missing data. These are unreported features, not evidence that a particular procedure was or was not used outside the registry entry. The absence of a posted analysis also means readers cannot assess whether the outcome definitions, populations, and analytic choices were implemented as prespecified.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abdominal pain (16.7%), febrile neutropenia (16.7%).

The registry reports serious adverse-event information for the group titled Patients With MPN. It records 6 participants at risk and 1 affected by a serious adverse event. For other adverse events, it records 6 at risk and 5 affected. The listed death count is 0. These are group-level counts; they should be read as registry safety summaries rather than as estimates of comparative risk.

Abdominal pain and febrile neutropenia are listed among the leading serious adverse-event terms, each at 16.7%. The record does not provide further event-level context in the registry record, such as timing, severity grading, relationship to a study drug, recurrence, or the number of events per affected participant. A term's listed percentage should not be interpreted as a treatment-attributable rate without that context. Nor does the absence of a reported death establish that serious harm was impossible.

In general, adverse-event counts describe events observed and recorded under the study's reporting approach. A small enrolled group provides limited information about less common events and about variation in risk. Because the study has no randomized comparator, these figures cannot establish whether the combination changed the frequency of adverse events relative to another treatment. The registry safety counts do not answer the primary response question.

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

The record establishes that a completed phase II, open-label, single-group study evaluated combined ruxolitinib and enasidenib in people with IDH2-mutated MPN or chronic-phase MF. It defines a primary response endpoint for treated accelerated-phase and blast-phase MPN participants, using CR, PR, or CRi under 2013 International Working Group criteria within 6 cycles. It also lists secondary response outcomes and selected safety counts. These are useful descriptions of the study question and the information entered in the registry.

However, the registry record does not report the primary response count. It therefore cannot show from the posted results how many primary-cohort participants met the response definition, how responses were distributed among CR, PR, and CRi, or how precise any response estimate would be. The stated study hypothesis that combination therapy might improve response is not a result. No comparative estimate can be derived from a design with no registered control group.

In general, a single-group response observation can provide descriptive evidence about outcomes in the treated participants, but it does not isolate the effect of treatment from other possible explanations. A controlled comparison is needed to estimate a direct treatment contrast. Even if a response count were available, interpretation would also depend on the cohort denominator, outcome assessment procedures, missing-data handling, and follow-up completeness; those details are not reported in the registry record.

The safety entries report 1 participant affected by a serious adverse event among 6 at risk, 5 affected by other adverse events among 6 at risk, and 0 deaths. They offer a narrow description of the recorded safety data, not a complete safety profile or evidence of comparative safety. The leading serious-event terms are listed at 16.7% each, but the registry does not provide all of the contextual details needed to attribute events or characterize their course.

The most defensible conclusion is therefore about what the registry documents: the study's design, intended response measure, and selected adverse-event counts. It does not report the primary efficacy result or an inferential analysis. The record cannot establish that the combination improved response, nor can it establish that it did not.

14. Why This Trial Matters Statistically

This trial illustrates why endpoint definitions and endpoint results must be distinguished. The registry specifies a response-based primary outcome, identifies the disease cohort to which it applies, and gives criteria for CR, PR, and CRi. Those details clarify what investigators intended to count. But without the number of participants meeting the definition, the registry entry cannot answer the efficacy question. A well-described endpoint is not itself an outcome finding.

The study also highlights the inferential limits of a single-group design. Such a design can describe outcomes in participants receiving a regimen, but it does not create a like-for-like comparison with an alternative. That distinction matters when a trial hypothesis uses language about improvement: improvement is inherently comparative, while a single-group count is descriptive unless additional assumptions or evidence support a comparison. No such additional analysis is reported in the registry record.

The small enrollment of 6 further emphasizes the need to report denominators and uncertainty, especially when response and safety outcomes are participant counts. In general, estimates based on few participants may be imprecise, and an individual outcome can have substantial influence on a summary. The registry does not report a primary response estimate or interval, so readers cannot assess that precision for efficacy.

Finally, the mismatch between the registered single-group design and the two-arm assumptions described for the sample-size illustrations is a useful reminder that planning calculations are conditional on their assumptions. They are not retrospective evidence that a study had a particular probability of success, and they do not substitute for the actual endpoint result. The registry record supports a careful account of the research question and design, while leaving the central efficacy outcome unreported.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several limitations specific to this trial constrain interpretation of the registry entry. Enrollment was 6, and the record does not report how many participants were in the primary accelerated-phase and blast-phase MPN cohort versus the chronic-phase MF group. The primary outcome denominator is therefore unavailable, as is the primary response count. The endpoint definition is detailed, but there is no posted efficacy result or estimate of precision.

The study is single-group and open-label, with no randomized comparator recorded. A comparison against an alternative treatment cannot be made from this design. The record also does not explain whether response assessment was blinded or independently reviewed. Since the primary endpoint involves clinical and morphologic criteria, absent assessment details leave uncertainty about how consistently those criteria were applied.

The registry does not report the sample-size justification, analysis populations, missing-data methods, or statistical-analysis plan. It does not state how participants without an evaluable response would be handled, nor whether sensitivity analyses were planned. It also does not report an interim-analysis plan. These omissions prevent assessment of the relationship between the intended design and the analyses actually performed.

Safety reporting is limited to the listed group counts and leading serious-event terms. The record does not include the contextual details needed to assess event timing, attribution, recurrence, or severity. With 6 participants at risk, the safety entries provide limited information about uncommon events. The status of completed does not resolve the absence of efficacy results, analysis details, or outcome-population denominators in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Combined Ruxolitinib and Enasidenib in Patients With Accelerated/Blast-phase Myeloproliferative Neoplasm or Chronic-phase Myelofibrosis With an IDH2 Mutation — NCT04281498.
• Registry record last updated 2025-02-04; status last verified 2025-01.
• Results first posted 2024-12-18.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry describes NCT04281498 as a completed phase II, open-label, single-group study of combined ruxolitinib and enasidenib in patients with accelerated-phase or blast-phase MPN, or chronic-phase MF, with an IDH2 mutation. Enrollment was 6. The recorded start date is 2021-01-14, and the primary completion date is 2023-05-30.

The primary outcome is the number of treated accelerated-phase and blast-phase MPN participants achieving CR, PR, or CRi within 6 cycles, assessed under 2013 International Working Group criteria. The registry record does not report the primary response count or an efficacy analysis. It reports serious adverse events in 1 of 6 at risk, other adverse events in 5 of 6 at risk, and 0 deaths. Abdominal pain and febrile neutropenia are each listed among leading serious-event terms at 16.7%.