Informative Censoring in Randomized First-Line Trials of Chronic Lymphocytic Leukemia
Authors: Simon Florian , Ligtvoet Rudy , Fürstenau Moritz , Langerbeins Petra , Fink Anna Maria , Von Tresckow Julia , Cramer Paula , Poulsen Christian Bjørn , Illmer Thomas , Müller Lothar , Vehling-Kaiser Ursula , Eckart Michael J. , Sivcheva Liliya , Loscertales Javier , Jentsch-Ullrich Kathleen , Hebart Holger F. , Levin Mark-David , Da Cunha-Bang Caspar , Kutsch Nadine , Tausch Eugen , Schneider Christof , Stilgenbauer Stephan , Robrecht Sandra , Kater Arnon P. , Niemann Carsten Utoft , Fischer Kirsten , Hallek Michael , Eichhorst Barbara F. , Al-Sawaf Othman 
Published: December 2024

BACKGROUND: Non-informative censoring occurs when censored survival times are similarly distributed in both experimental and control arms of a randomized controlled trial (RCT). However, if the risk of drop-out is not evenly distributed, e.g. because patients withdraw consent in one arm of a trial more frequently, informative censoring is present and survival estimates might be biased. Previous analyses have suggested a censoring imbalance between study arms of large systemic RCTs in oncology (Gilboa et. al, Eur J Cancer, 2021). In chronic lymphocytic leukemia (CLL), the prevalence of informative censoring is unknown since no comprehensive analyses of censoring within large RCTs have been conducted so far.

METHODS: Data from four German CLL Study Group (GCLLSG) trials with detailed censoring documentation (including regular versus early end-of-study censoring) and consisting of 1806 patients were extracted from the GCLLSG database. Included trials were CLL12, GAIA/CLL13, CLL14 and CLLM1 which tested novel agents vs. placebo (CLL12, M1) or vs. chemoimmunotherapy (CIT) (CLL13, 14).

To confirm these results in external studies, published randomized phase III trials from the last 20 years were analyzed for informative censoring. Censoring data was extracted from the most recent publication in which censoring events were depicted using WebPlotDigitizer (Version 4.5, Rohatgi, 2021). Trials with published results without clear censoring marks were excluded. The external cohort comprised eight trials and 3464 patients. Treatment consisted of targeted treatment vs. CIT (ILLUMINATE, GLOW, ELEVATE-TN, FLAIR2021 and FLAIR 2023, RESONATE-2 and SEQUOIA), apart from the COMPLEMENT-1 trial, which compared two CIT approaches.

To estimate the difference in risk of censoring between treatment arms, reverse Kaplan-Meier methodology and Cox proportional hazards regression analysis were used with censoring as an event. Sensitivity analyses examined a possible impact of censoring imbalances on observed treatment effects by ‘bootstrapping’ the censored survival times under the assumption of non-informative censoring.

RESULTS: Within three (75%) GCLLSG trials there was no indication of informative censoring for PFS with HRs for censoring: CLL12 (ibrutinib vs. placebo in early stage CLL) HR 1.16 (95%CI 0.82 - 1.64, p=0.39); CLL14 (Ven-Obi vs. Clb-Obi) HR 1.28 (0.92 - 1.77, p=0.15), CLL-M1 (lenalidomide vs. placebo maintenance) HR 3.03 (0.68 - 13.52), p=0.15).

Reverse-KM analysis for PFS of the external dataset likewise did not show significant differences in censoring in five (63%) external trials with HRs for censoring: ELEVATE-TN (acala and acala-obi vs. clb-obi) 0.93 (0.71 - 1.22, p=0.61) and HR 0.89 (0.68 - 1.17, p=0.41 ) and, FLAIR2021 (IR vs. FCR) HR 1.08 (0.92 - 1.27, p=0.35), FLAIR2023 (IV vs. FCR) HR 1.01 (0.83 - 1.22, p=0.93), RESONATE-2 (ibrutinib vs. clb) HR 0.76 (0.44 - 1.31, p=0.32), SEQUOIA (zanu vs. BR) HR 0.94 (0.77 - 1.15, p=0.55).

In GAIA/CLL13 significant differences in the risk for censoring were apparent in the analyses of early-EOS (excluding deaths) with HR for censoring of PFS for RVe, GVe and GIVe vs. CIT of 0.13 (95% CI 0.04 - 0.42, p=0.001), 0.04 (0.01 - 0.32, p=0.002) and 0.22 (0.08 - 0.57, p=0.002), mostly due to 13 patients dropping out after treatment allocation to the CIT arm, before starting therapy.

In the external dataset, the reversed PFS-analysis of the ILLUMINATE, COMPLEMENT-1 and GLOW trials showed a significantly higher risk of censoring in the control arm with HRs of 0.50 (95% CI 0.33 - 0.77, p-0.001), 0.34 (0.21 - 0.56, p&lt;0.001) and 0.52 (0.32 - 0.85, p=0.009), respectively.

Sensitivity analysis showed that observed and boot-strapped HRs were similar for both trials with as well as without imbalanced censoring, indicating that informative censoring did not substantially influence PFS or OS, with no substantive differences found for the treatment effects.

CONCLUSION: A minority of large randomized CLL trials show signs of imbalanced censoring between study arms, suggesting that informative censoring is not a common confounder in randomized CLL trials. In trials with an indication of censoring imbalances, these were limited to control arms with CIT in periods where targeted treatment outside the clinical trials would be available to most patients. Encouragingly, sensitivity analysis did not show a substantial impact on treatment effects.