Acalabrutinib for the Treatment of Relapsed or Refractory Autoimmune Hemolytic Anemia in Patients With Chronic Lymphocytic Leukemia: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Acalabrutinib for the Treatment of Relapsed or Refractory Autoimmune Hemolytic Anemia in Patients With Chronic Lymphocytic Leukemia (NCT04657094), a na phase 2 study. The primary outcome is Autoimmune Hemolytic Anemia (AIHA) - Overall Response Rate (ORR).

2. Clinical Question

The study asks whether participants with chronic lymphocytic leukemia and relapsed or refractory autoimmune hemolytic anemia achieve a complete or partial response during treatment with acalabrutinib. The registry describes a single-group study, so it does not set up a concurrent comparison with another treatment or a control group. The primary outcome is an overall response rate, but the registry record does not report the response result or its confidence interval.

3. Trial Design

This is a phase 2, single-group trial sponsored by City of Hope Medical Center. The registry lists an enrollment of 4 and an allocation of not applicable. It records no masking. Because all participants are assigned to the acalabrutinib treatment group and there is no comparator arm, the design is not a randomized treatment comparison.

The treatment description specifies acalabrutinib by mouth twice daily on days 1-28, repeated every 28 days for up to 12 cycles unless disease progression or unacceptable toxicity occurs. It says treatment may continue beyond 12 cycles for a maximum of 36 cycles, with continuation dependent on the treating physician’s opinion. The registry’s continuation wording is incomplete, so further conditions are not reported in the registry record.

The record lists a start date of 2021-03-16, a primary completion date of 2023-04-01, and a status of active, not recruiting. It lists one primary outcome measure, overall response rate, and no analyses. The endpoint description names a complete or partial response and specifies an exact confidence interval and an exact binomial test against a null rate. However, numerical outcome results and analysis outputs are not reported in the registry record.

The primary outcome timing is described in two ways: assessment at the end of the 6-week therapy and response at 6 cycles. These descriptions do not align on their face, and the record does not explain how they relate. The study’s small enrollment and lack of a comparator also mean that any interpretation must remain focused on the participants observed in this single group, rather than on a treatment effect relative to another option.

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

Analysis population for the primary outcome, as defined in the registry: Among the 4 enrolled participants, one was in-evaluable for not finishing 6 cycles of the study treatment due to toxicity.

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 Autoimmune Hemolytic Anemia (AIHA) - Overall Response Rate (ORR), measured over Participants were assessed at the end of the 6-week therapy..

The primary endpoint is the overall response rate for autoimmune hemolytic anemia. The registry defines an overall response as the proportion of patients achieving either a complete response or a partial response. This binary outcome classifies each participant according to whether the stated response criterion was met, then expresses the result as a percentage of participants in the relevant analysis population.

A response rate is used to describe how often a prespecified outcome occurs in a group. It is not, by itself, a comparison of treatments. In this single-group study, the endpoint can describe response among participants who are included in the analysis, but it cannot establish how that response rate compares with what would have occurred under another treatment or without acalabrutinib.

The registry specifies an exact 95% confidence interval for the response rate and an exact binomial test against a null hypothesis of a 30% rate, using a one-sided alpha of 0.05. The endpoint description refers to response at 6 cycles, whereas the timeframe states that participants were assessed at the end of the 6-week therapy. The record does not clarify this difference. It also does not report the observed response rate, confidence interval, or test result, so the endpoint’s numerical result and precision cannot be assessed from the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry specifies a percentage endpoint, an exact confidence interval, and an exact binomial test. These methods are suited to a binary outcome, where each participant is classified as having achieved a response or not having achieved a response. The registry does not report the observed classifications or any analysis output, so the following explains the stated methods rather than interpreting a calculated result.

What does a response rate represent?

A response rate is the number of participants meeting the response definition divided by the number included in the analysis, expressed as a percentage. The response definition combines complete and partial response. The denominator matters: it could depend on the analysis population and on the handling of participants whose response cannot be evaluated. Although the registry says one participant was unevaluable because of toxicity-related treatment discontinuation, it does not report how that participant was treated in the endpoint analysis. The observed response rate therefore cannot be derived from the record.

What does the confidence interval add?

General statistical explanation: a confidence interval communicates the uncertainty associated with an estimate. For a binary outcome, the interval is related to the observed response count and the number of participants analyzed. An exact interval uses the binomial probability model rather than relying on a normal approximation to the response-rate distribution. This can be useful when the amount of data is limited, although an interval may still be wide when there is little information. The registry specifies an exact 95% confidence interval, but its numerical bounds are not reported in the registry record.

A confidence interval is not a treatment comparison, and it does not correct for the absence of a control group. It describes uncertainty around the response rate estimated in the analyzed group under the method’s assumptions. It should be read alongside the endpoint definition, assessment time, response count, and analysis denominator. Those results are not reported in the registry record, and the outcome timing is described both as the end of the 6-week therapy and as 6 cycles.

What is the exact binomial test asking?

The registry specifies an exact binomial test against a null hypothesis of a 30% response rate, with a one-sided alpha of 0.05. General statistical explanation: a binomial test evaluates how compatible an observed count of responses is with a specified response probability, assuming the binary outcomes and analysis population are defined. An exact test calculates probabilities using the binomial model rather than an approximation. The significance level is a prespecified threshold for judging evidence under the test; it is not the probability that the null hypothesis is true.

The registry says the test was intended to determine whether the rate at 6 cycles was disappointing or promising. The record does not report the observed count, p-value, or the investigators’ conclusion. The stated null rate and testing threshold describe the plan, not evidence that the outcome met a criterion. A one-sided test addresses a prespecified direction, but the registry wording does not further explain the direction or how the decision labels were operationalized.

Why does the single-group design matter?

General statistical explanation: random allocation and a concurrent comparator can help distinguish differences associated with treatment from differences that arise from participant characteristics, time, or other influences. This trial is recorded as single-group, with no allocation and no masking, and it has no comparator arm. Thus, even if a response rate were reported, it would describe outcomes in the treated group and would not estimate a randomized contrast against another treatment.

The registry’s sample-size assumptions describe planning illustrations based on a fraction of the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Those assumptions are not the trial’s recorded single-group design and should not be mistaken for its analysis plan or its actual design justification. The illustration values themselves are not reported in the registry record. Such planning calculations are not observed power, and they cannot substitute for the trial’s outcome estimate or its confidence interval.

Over-dispersion is a general concern when outcomes vary more than a chosen statistical model expects. For a simple binary response endpoint, the key interpretation points are the response definition, denominator, observed count, and uncertainty method. The registry does not report a model for over-dispersion or a more elaborate analysis; no such method should be assumed. The outcome analysis itself is also not reported in the registry record.

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("Treatment (Acalabrutinib)")
n      <- c(3)
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  Treatment (Acalabrutinib)  3  2  66.7  9.4  99.2  20.8  93.9  19.4  93.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome measure, overall response rate, and no analyses. It does not report whether there were additional planned comparisons, interim analyses, or a multiplicity adjustment strategy. These details are not reported in the registry record, so the listed endpoint alone cannot establish how the study handled the possibility of multiple statistical questions.

The primary endpoint description identifies a complete or partial response as the outcome and specifies a test against a 30% null rate. However, the record does not report a response count, analysis denominator, confidence interval, p-value, or analysis population. It states that one of the 4 enrolled participants was unevaluable because toxicity prevented completion of 6 cycles, but it does not say whether that participant was excluded, counted as not responding, or handled another way. The missing-data method is not reported in the registry record.

The endpoint’s assessment timing is also unclear: the timeframe says the end of the 6-week therapy, while the description refers to response at 6 cycles. The record does not explain whether these refer to the same assessment or different points. This affects which observations belong in the endpoint assessment and cannot be resolved from the recorded information.

Without a defined analysis population and missing-data rule, the intended denominator for the response rate is unknown. Without a multiplicity plan, the interpretation of any eventual statistical test in the context of other analyses would also be uncertain. Since no analyses are listed, there are no reported analysis outputs to evaluate for these issues.

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: dress syndrome (25.0%), covid-19 (25.0%).

The registry lists 4 participants at risk for serious adverse events and 2 affected. It also lists 4 participants at risk for other adverse events and 4 affected. The death count is 0. These are descriptive counts in the acalabrutinib treatment group; they do not establish that the treatment caused an event or that an event was unrelated to treatment.

The listed top serious adverse event terms are DRESS Syndrome at 25.0% and COVID-19 at 25.0%. The registry record does not give event-level details, timing, duration, severity grades, or causal attribution in the registry record. The percentages should be read as reported, not as evidence of a comparative risk, because there is no control group. They also do not replace review of the full safety record, including definitions and participant-level context.

Serious adverse event counts and other adverse event counts describe different categories; they should not be combined. The registry does not report further details that would clarify overlap between categories or explain the events. The small enrolled group also means these figures are descriptive of this study group, not a precise estimate of safety frequency in a broader population.

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

The record establishes that a phase 2, single-group study was conducted to assess acalabrutinib for relapsed or refractory autoimmune hemolytic anemia in patients with chronic lymphocytic leukemia. It defines overall response as complete or partial response and specifies an exact confidence interval and a test against a 30% null rate. These details explain the intended clinical question and statistical framework.

The record does not establish the observed response rate. It contains no analysis results, and the numerical response count, confidence interval, and test result are not reported in the registry record. Therefore, the posted information cannot show whether any particular response criterion was met, how precise an estimate was, or whether the planned test supported a conclusion. The fact that a statistical test was specified does not itself constitute evidence of an effect.

Even if response results were available, the single-group design would describe outcomes among treated participants without providing a randomized comparison. It would not by itself show what would have happened to a comparable group under another treatment or without acalabrutinib. The registry’s sample-size illustrations are planning calculations, not observed power and not treatment-effect evidence.

The record also identifies one participant as unevaluable because toxicity prevented completion of 6 cycles, without reporting the rule used to handle that participant in the endpoint analysis. Its two descriptions of endpoint timing—at the end of the 6-week therapy and at 6 cycles—are not reconciled. These uncertainties matter because the denominator, missing-data handling, and assessment time help define the response estimate.

Accordingly, the appropriate reading is limited to the study’s design, endpoint, and reported safety counts. A response conclusion, comparative treatment claim, or precise estimate of benefit cannot be drawn from the outcome information reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates why a planned endpoint and a reported result are different kinds of information. The registry defines a clinically interpretable binary outcome—complete or partial response—and specifies an exact confidence interval and test. Those details clarify what investigators intended to measure. But with no outcome analyses reported, the response rate and its precision remain unknown. A statistical plan cannot substitute for the counts and estimates produced by applying that plan.

It also demonstrates how analysis populations affect even a straightforward percentage. The registry reports 4 enrolled participants and notes that one was not evaluable after toxicity prevented completion of 6 cycles. Without a stated denominator or a missing-data rule, readers cannot tell how the endpoint rate would be calculated. Reporting the response count, analysis population, and handling of unevaluable participants is essential for interpreting a binary outcome.

The record’s assessment timing language is another important statistical detail. The timeframe refers to the end of the 6-week therapy, while the endpoint description refers to 6 cycles. A clear, consistent assessment time is necessary to understand which outcomes contribute to the estimate and how it relates to treatment exposure.

Finally, the single-group design shapes the inference. A response rate in one treated group can be descriptive, but it cannot isolate a treatment effect through a concurrent randomized contrast. The stated null rate and test do not create a comparator group. These distinctions help prevent a planned analysis, a single-group observation, or an unreported result from being read as comparative evidence.

15. Limitations

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

The main limitation in interpreting this trial from the registry record is the absence of outcome analyses. The record does not report the response rate, response count, confidence interval, or test result. Without those, neither the direction nor precision of the primary endpoint can be assessed.

The enrolled group is listed as 4 participants, and one was described as unevaluable because toxicity led to not finishing 6 cycles. The registry does not report the endpoint denominator or how the unevaluable participant was handled. This leaves the analysis population and missing-data approach unclear. In general, estimates from a small group can be sensitive to individual outcomes, but the actual response estimate and its uncertainty are not available.

The primary endpoint timing is described as assessment at the end of the 6-week therapy and also as response at 6 cycles. The registry does not reconcile those descriptions. The treatment schedule is given in cycles, but the endpoint timing remains ambiguous as recorded.

The study is single-group, has no allocation, and has no masking. With no comparator, observed outcomes cannot be interpreted as a randomized treatment difference. The registry also does not report a multiplicity strategy, interim-analysis plan, or detailed statistical analysis population. Further, the continuation wording for treatment beyond 12 cycles is incomplete. These limitations constrain interpretation of both efficacy and safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Acalabrutinib for the Treatment of Relapsed or Refractory Autoimmune Hemolytic Anemia in Patients With Chronic Lymphocytic Leukemia — NCT04657094.
• Registry record last updated 2026-05-06; status last verified 2026-04.
• Results first posted 2024-05-29.
• 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 record describes a phase 2, single-group study sponsored by City of Hope Medical Center. It lists 4 enrolled participants and a status of active, not recruiting, with a start date of 2021-03-16 and a primary completion date of 2023-04-01. The intervention is acalabrutinib, taken by mouth twice daily on days 1-28 in repeating 28-day cycles.

The primary outcome is autoimmune hemolytic anemia overall response rate, defined as the proportion achieving complete or partial response. The registry specifies an exact 95% confidence interval and an exact binomial test against a 30% null rate, using a one-sided alpha of 0.05. It notes one participant was unevaluable because toxicity prevented completion of 6 cycles, but does not report the analysis denominator or handling rule. No analyses or numerical primary outcome results are reported in the registry record. The endpoint timing is described both as the end of the 6-week therapy and as 6 cycles.

The safety record lists 2 participants affected by serious adverse events, 4 affected by other adverse events, and 0 deaths. DRESS Syndrome and COVID-19 are each listed among the top serious terms at 25.0%.