An article published in Annals of Oncology described the design of a phase 3 sequential multiple assignment randomized trial (SMART) for the evaluation of multistage ibrutinib-based treatment approaches for previously untreated older patients with chronic lymphocytic leukemia (CLL).

Although the efficacy and safety of the ibrutinib in patients with CLL has been demonstrated, most patients receive continuous treatment until disease progression. However, deeper responses potentially achieved with ibrutinib-based combination regimens (eg, involving CD20 inhibitors, such as rituximab and obinutuzumab) may allow for treatment discontinuation in selected patients (ie, those who achieve minimal residual negative disease with complete remission [MRD-negative CR]). Hence, the need for clinical trials that both compare different ibrutinib-based regimens in CLL and also allow for “adaptive interventions defined by an individual’s sequence of treatment decisions and guided by intermediate outcomes, such as response to therapy.”   

The proposed phase 3 SMART study described in this article was designed to answer both of the following specific questions in the setting of untreated CLL in older patients (≥70 years):

Continue Reading

  1. Does limited frontline treatment with combination therapy using ibrutinib/the Bcl-2 inhibitor, venetoclax/obinutuzumab (IVO) and ibrutinib maintenance (IM) have superior progression-free survival (PFS) compared with limited frontline treatment with ibrutinib plus obinutuzumab (IO) and IM?
  2. Does the treatment strategy of IVO plus IM for patients without MRD-negative CR and IVO plus IM discontinuation for patients with MRD-negative CR have superior long-term PFS compared with IO plus IM for all patients?

Specifically, patients would initially be randomly assigned in a 1:1 ratio to receive either first-line IVO or IO as the first-stage intervention, and all patients would be evaluated for MRD status and response. As the standard of care, all patients in the IO arm would receive IM as the second-stage intervention, regardless of the presence or absence of MRD-negative CR. However, in the IVO arm, the second-stage intervention would be determined by MRD-negative CR status; patients without MRD-negative CR status following IVO would receive IM, whereas those achieving MRD-negative CR would be re-randomized (ensuring balanced patient characteristics) in a 1:1 ratio to receive either IM or undergo IM discontinuation.

Related Articles

“Trials with SMART designs are suitable for the discovery of which sequential treatments work better than standalone treatments and can be used to investigate the interplay between treatment strategies and disease development” and “data from a SMART design can be used to simultaneously address the effectiveness of treatments at each stage of the trial as well as the effectiveness of the overall embedded treatment regimens,” the authors wrote.

For example, the proposed SMART schema evaluating 3 embedded regimens in 2 stages makes it possible to compare the following: IO plus IM for patients with and without MRD-negative CR; IVO plus IM for patients with and without MRD-negative CR; and IVO with or without IM for patients with MRD-negative CR. In addition, whether an approach involving more aggressive initial therapy (IVO) followed by therapy discontinuation for those achieving MRD-negative CR is superior to less aggressive therapy (IO) followed by IM for all patients could be evaluated.

“In randomized trials that guide patient treatment based on an intermediate outcome, a SMART design can be used to identify appropriate treatment strategies while maintaining statistical rigor and should be considered,” the authors concluded.


  1. Ruppert ASYin JDavidian M, et al. Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia [published online February 25, 2019]. Ann Oncol.  doi: 10.1093/annonc/mdz053