ASH 2021 | BELINDA: Tisagenlecleucel in B-cell NHL

I was honored to represent my fellow investigators for the BELINDA trial. So BELINDA is looking at patients with advanced B-Cell non-Hodgkin’s lymphoma, who either failed to respond to first line therapy or had progression or relapse of disease within 12 months of therapy. For this patient population, the outcomes are very, very poor. The standard of care in this situation would be second line chemotherapy and if the patients had responsive disease move on to an autologous stem cell transplant. Unfortunately less than 40% of patients will be found to have chemosensitive disease and make it to autologous stem cell transplantation. Even in that situation the results are relatively poor as such novel treatments are needed for this poor risk group of patients. In BELINDA, we looked at the use of tisagenlecleucel, which has been demonstrated to result in prolonged progression-free survival in more advanced patients with non-Hodgkin’s lymphoma, after who had progressed or failed to respond after at least two lines of therapy.

Our hypothesis was that based upon those results, if we moved it up front, that it would result in improved outcomes for this high-risk group of patients who fail or progress early after first line therapy. So the one arm was tisagenlecleucel versus the standard of care and this trial involved 322 patients who are randomized on a one to one basis, either to tisagenlecleucel or the standard of care with the goal of autologous stem cell transplantation. It involved both US and non-US sites. Matter of fact, approximately 30% of patients were treated in the US and 70% were at international sites. The primary endpoint was event-free survival as defined as the 12-week assessment mark and then the idea behind using a 12-week assessment was used based upon the CORAL trial, where patients on standard of care could go on to receive a second line of therapy or a third-line of therapy, if they didn’t respond to second line of therapy.

Unfortunately, and quite surprisingly to the investigators, event-free survival was equal between the two arms, matter of fact, median event-free survival was 3.0 months on both arms. We looked at this as potentially attributed to a number of factors. The most important might be that the time from randomization to the time of tisagenlecleucel infusion was 52 days. This is really a long time in this very aggressive patient population and there’s a number of explanations that could be given to that. One of them is that we did allow multiple lines of chemotherapy as bridging therapy, which is different than some of the other trials that were presented here at ASH this year. Another significant difference was the dosing of the lymphodepleting chemotherapy. In the BELINDA trial cyclophosphamide was dosed at 900 milligrams per meter squared over three days and fludarabine 75 milligrams per meter squared over three days.

In other trials doses on level 1500 milligrams per meter squared for cyclophosphamide and 90 milligrams of fludarabine per meter squared were used. We actually think lymphodepleting chemotherapy is extremely important, probably and more importantly, in this patient population, which hasn’t seen a lot of chemotherapy beforehand. Although the results were equivalent, we hope that the number of the things that we looked at would be studied and can be used for future CAR-T cell trials. So for at least how we design the BELINDA trial that tisa-cel is equivalent to the standard of care of second line chemotherapy and autologous stem cell transplantation. That infusion of cells as soon as possible is probably a key factor in the success of this treatment in this specific patient population and that we need to have better ways to get disease under control prior to CAR-T cell infusion.