William Wierda, MD, PhD: Let’s move on to treatment for relapsed chronic lymphocytic leukemia. There was a 4-year update yesterday here at ASH [the American Society of Hematology annual meeting] 2019 by John Seymour, MBBS, PhD, a 4-year update on the MURANO study. Maybe, Stephen, you can summarize what that update told us about the MURANO study and outcomes for patients treated with venetoclax in the relapsed setting.

Stephen Opat, MBBS: The MURANO study was a randomized phase III study comparing bendamustine, rituximab, or Rituxan, with the experimental arm of venetoclax with rituximab. It was a fixed duration of 2 years of treatment, and what was really impressive about this study is not only was the experimental arm vastly superior in terms of both progression-free and overall survival, but there was a high rate of MRD [minimal residual disease]-negativity in the pretreated population. So patients who received prior treatment, they’ve got adverse biologic features, there are high rates of 17p loss, TP53 mutation. And so, to achieve MRD-negativity in this group of patients is a tough job.

And it does seem to be in patients, even with adverse biological features, if they attained MRD-negativity, they often had quite a durable treatment-free interval. So, it does look like a useful combination. The one problem with the MURANO study is it was largely done before patients had been treated with ibrutinib, so we don’t have data on whether that strategy is useful in people who’ve received frontline BTK [Bruton tyrosine kinase] inhibitors.

William Wierda, MD, PhD: Dr Ma, you were involved in the trial that preceded the MURANO trial, the M13-365, the phase Ib clinical trial. If we’re talking about fixed-duration therapy, I think the concept of re-treatment and whether patients are expected or anticipated to respond to re-treatment, I think that the original trial allowed for patients to come off treatment, and then there were patients who were re-treated when they progressed or relapsed. Maybe you could give us some idea about what’s been seen with that and what are the thoughts on re-treatment after relapse with a fixed-duration regimen.

Shuo Ma, MD, PhD: Right. In the original phase Ib study, the protocol was written that once patients are able to achieve either an undetectable MRD status or a complete remission, then they have the option of either continuing on the single agent venetoclax, or to stop treatment and then be allowed to be re-treated if they have progression later on. So, we have patients who were continued on the treatment, and we have patients who actually stopped the treatment. And at ASH 2019, we have updated data from the study, so that will be interesting to see. But for patients who stopped treatment, we do have a few patients who actually progressed and restarted on treatment. And when we’re restarting on treatment, we’re doing venetoclax plus 6 months of rituximab again.

Most of those patients actually were able to achieve initial response. One patient did later on progress after starting on the treatment again. But the other, I think 7 or 8 patients, were still able to continue on the treatment and maintain a response. So re-treatment is definitely a potential feasible strategy.

William Wierda, MD, PhD: And we don’t anticipate that they’re necessarily going to be refractory to treatment when we initiate subsequent or re-treatment.

Shuo Ma, MD, PhD: At least not so far from the data we have, but it’s a very small number of patients, and I think that’s something that needs to be tested in the clinical trial.

Transcript Edited for Clarity