Challenges in handling allogeneic stem cell transplantation in randomized clinical trials

In randomized clinical trials (RCTs) for hematological malignancies, patients may undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT) as part of standard clinical pathways. Allo-HSCT is a potentially curative but high-risk procedure performed after randomization and thus constitutes an important intercurrent event that can substantially influence survival outcomes. However, its handling in statistical analyses is not standardized.

To review current statistical methods used to handle postrandomization allo-HSCT as an intercurrent event in RCTs, and to highlight how each method corresponds to a different estimand, reflecting distinct clinical questions.

We reviewed 93 RCTs published between January 1, 2014, and April 1, 2024 that reported survival outcomes with postrandomization allo-HSCT.

Three different statistical methods were employed to estimate the treatment effects: censoring at the time of allo-HSCT (64 analyses), a time-dependent covariate in a Cox model (24 analyses), or ignoring allo-HSCT status (17 analyses). Each method estimates the treatment effect in response to a different clinical question and estimand, with specific assumptions that must be considered when interpreting the results. Censoring corresponds to the "hypothetical" estimand, but its validity requires 2 things: first, that the likelihood of receiving allo-HSCT is similar across treatment arms; and second, that patients who undergo transplantation have a similar prognosis to those who do not. Time-dependent covariate incorporates the effect of allo-HSCT but is not associated with a specific estimand and requires careful interpretation. Ignoring allo-HSCT corresponds to the "treatment policy" strategy, of comparing the treatment strategy, whichever allo-HSCT or not, without additional assumptions.

There is no consensus on handling allo-HSCT as an intercurrent event in survival analyses. Censoring, although common, may introduce bias if treatment or prognostic covariates influence allo-HSCT use. The treatment policy estimand should be preferred when allo-HSCT is part of the therapeutic strategy.