CLL/SLL

Results from a meta-analysis in CLL: model supports MRD as primary endpoint in CLL chemo-immunotherapy trials

On December 18, 2017, Natalie Dimier of Basel, Switzerland and colleagues published online in Blood, a meta-analysis of three randomized, phase III clinical trials. The objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemo-immunotherapy as a surrogate endpoint for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL). Data were collected from three, phase III clinical trials (NCT00281918, NCT00769522, NCT01010061).

Highlights:
  • Of 2,162 trial patients randomized, data for peripheral blood minimal residual disease (PB-MRD) or early progressive disease or death were available for 393, 337, and 474 patients in CLL8, CLL10, and CLL11, respectively
  • In all three studies, MRD was assessed in PB in all patients and in BM only in patients with complete response (CR)
    • Primary endpoint of each trial was investigator-assessed PFS
  • Meta-regression model predicted treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively
  • Model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS
    • As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed
    • For each unit increase in the (log) ratio of MRD-negative rates between arms, the log of PFS hazard ratio (HR) decreased by -0.188 (95% confidence interval, -0.321 to -0.055; P = 0.008)
  • Across the trials, PFS was longer and a larger proportion of patients achieved MRD negativity in the experimental arm vs control arm
  • Statistically significant slope parameter indicates that an increase in MRD response relative risk between trial arms is associated with improved PFS outcomes

This analysis was done to determine whether the treatment effect on MRD response in PB at the end of induction treatment with chemo-immunotherapy can predict treatment effect on PFS in patients with CLL. To this end, the investigators employed PB- MRD data from three randomized, phase 3 trials to determine the relative strength between treatment effects using a meta-regression model. To this end, this meta-analysis demonstrated a statistically significant relationship between treatment effects on PFS and MRD. This model gives credence to the use of MRD as a primary endpoint in CLL chemo-immunotherapy clinical trials.

References
  1. Dimier N et al. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate endpoint in CLL. Blood. 2017 Dec 18 pii: blood-2017-06-792333. doi: 10.1182/blood-2017-06-792333. [Epub ahead of print]
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