ASH 2014

Post-transplant survival boosted by brentuximab vedotin in lymphoma

Dr Craig Moskowitz - Memorial Sloan Kettering Cancer Center, New York, USA

The patient population that were studied were patients who had relapsed or refractory disease. All these patients in theory are eligible to get an autologous stem cell transplant in the curative setting. If one looks at data over the past 25 years, about 50% of patients are cured with an autologous stem cell transplant for Hodgkin lymphoma. That curve has been at a plateau. There have been many studies that have been looked at over the years and all of them pretty much are negative.

And the reason for trying an anti-CD30 agent was what?

Brentuximab vedotin is approved in patients where stem cell transplant fails. It’s now being studied in a variety of settings in Hodgkin lymphoma, in the untreated setting before transplant and this study was looking at giving brentuximab vedotin in a random assignment fashion after a stem cell transplant. The study was designed in 2009 and at the time no patients had previously received brentuximab prior to a stem cell transplant. So the goal of this study was to see if we can improve progression free survival in patients who, in theory, were at risk to fail a stem cell transplant. We designed prognostic factors based upon getting together lymphoma experts. We picked three, these three risk factors have been shown to move the bar down. Patients who had any of these risk factors have a two out of three chance of being cured; patients with multiple risk factors have a one out of three chance of being cured. We wanted to move the bar up by giving brentuximab after a stem cell transplant so that’s what we did.

So what were your primary endpoints?

The primary endpoint was an improvement in progression free survival at two years with a pre-set criteria of between 10-15%. The reason we picked two years is that if you look at a host of peer reviewed studies in the literature, those patients in remission at two years after a stem cell transplant, between 90-95% of those patients will never relapse, so the curves are flat. So in this study the placebo arm at two years has a progression free survival of 45%, the same as everything else that has been reported in the literature. The study arm where patients received brentuximab for up to sixteen doses have a two year progression free survival of 65%. So that’s the bottom line – two-thirds of patients appear to be cured with this treatment and, in my opinion, it will be the benchmark for future studies.

So you have done… in a nutshell, what is it that you have done with this drug?

We’ve given it to patients after a stem cell transplant, every three weeks up to sixteen times. Likely what has happened is that we cured the patients who were likely to relapse between 9 and 18 months after a stem cell transplant; those patients who are almost going to be transplanted but relapse; the patients who are destined to do very poorly, unclear if those patients should even get an autologous stem cell transplant. So I think that we’ve moved the bar quite high.

So you have, let me get this straight, got a 20% difference in the rates of reaching two years.

The time to progression at two years is 20% improved with the addition of brentuximab after a stem cell transplant.

What about overall survival?

Overall survival, it’s too soon to look at overall survival; the study will read out through 2016. So when we designed the study back in 2009 the median survival for patients where stem cell transplant fails, this is data from Memorial and data from Stanford, is about 28 months. It turns out, though, that the median survival of patients now, in 2015, where stem cell transplant fails, just because of all the novel agents that are available, is probably approaching four years. But it’s very clear to understand that if a patient fails an autologous stem cell transplant they will die of Hodgkin lymphoma. We’ve shifted that curve from 28 months to 48 months but if you are not in remission at two years after an auto-transplant for Hodgkin lymphoma you are not going to be here five to seven years later. It will not happen.

And although you made a big difference to the progression of the disease, could you explain very briefly why it is that the overall survival at two years is not impacted?

The study is a crossover design; we allowed the placebo arm patients to get brentuximab at the time of relapse.

So what are the clinical messages for doctors coming out of this?

Based upon the treatment, the patients who are enrolled on this study and they are three cohorts of patients, the first are any patient who had a remission duration of less than one year with primary therapy; the second is any patient who did not go into remission with primary therapy and the third is any patient who has disease outside of the lymph node system, for example lung, liver or bone. Those three cohorts of patients were enrolled in this study and those three cohorts of patients, I believe, should be eligible to get maintenance or a consolidated brentuximab vedotin after a stem cell transplant once this is published.

Do you regard this as a paradigm change in treatment?

It’s the only positive study ever done in relapsed and refractory aggressive lymphoma in patients getting transplants. I’ve been doing transplants now since 1993 in all aspects of aggressive lymphoma. The two most important, Hodgkin lymphoma and diffuse large B-cell lymphoma, every single transplant study is negative but this one.

And if you were to sum up in just a few words what the take home message for doctors is, what would that be?

If you refer your patient for an autologous transplant to a transplant centre and they have one of these three risk factors, when you get them back you should be administering brentuximab vedotin in a standard fashion after the transplant.