This trial, the ECOG-ACRIN 4151 study, was a clinical trial that was designed to test whether autologous transplant in first remission for patients with mantle cell lymphoma benefit from that procedure compared to proceeding to maintenance therapy without a stem cell transplant, dependant upon whether patients had achieved what we call a minimal residual disease negative remission at the time of their evaluation for transplant.
What did your study find?
The study design was somewhat complex. There were four main groups in the trial. All patients were treated with a rituximab-based induction treatment regimen, mostly chemotherapy in addition to rituximab but some with novel agents such as a Bruton’s tyrosine kinase inhibitor in a minority of patients. The chemotherapy backbone was left to the discretion of the treating physician and was largely centre dependant.
Patients who achieved complete remission with their initial induction therapy also had undergone testing to determine whether a marker for minimal residual disease was detectable from a sample of their original lymphoma biopsy tissue at the time of their diagnosis. For patients who had such a marker detected, they were then screened for the persistent presence of that marker when other conventional measures of remission such as imaging studies or bone marrow biopsy didn’t detect any evidence of residual disease after they completed their induction course. For patients who tested negative for minimal residual disease even by that PCR-based molecular marker, those patients were randomised to either undergo consolidation with high dose chemotherapy and autologous stem cell transplant, which has been the long-standing standard of care for patients with mantle cell lymphoma who are younger and medically fit, or to bypass the transplant step in their treatment and to proceed directly to maintenance therapy with rituximab.
I should mention that following transplant patients also received rituximab maintenance and the duration of rituximab maintenance was 2-3 years, depending on location and regional practice patterns.
Those were the two primary groups and the main comparison in the study: patients achieving complete remission who also tested negative for minimal residual disease and were randomised to either transplant followed by rituximab maintenance or no transplant and only rituximab maintenance. The other two groups in the study were those who did not achieve remission by conventional testing or who achieved remission but still had a detectable level of minimal residual disease by the PCR-based molecular study or patients whose minimal residual disease could not be measured because they did not have an evaluable marker that was documented from their baseline tissue. So those two groups all were referred for transplant, there was no randomisation step in those cases.
The primary findings of the trial were that there was no difference in progression free or overall survival for those patients who were randomised to either transplant followed by rituximab maintenance or no transplant and rituximab maintenance only in first remission with negative minimal residual disease.
What are the implications of these findings?
The results of this study are important in that it dovetails with the findings of another recently reported randomised controlled trial in mantle cell lymphoma demonstrating that for at least a subset of patients there appears to be no benefit to the incorporation of autologous transplant as part of front-line therapy.
It’s important to understand the historical context in which we have done this procedure for patients with mantle cell lymphoma. It goes back to the early 2000s at a time when the median survival for patients with mantle cell lymphoma was relatively short, about 3-4 years, and the induction regimens that we used to treat patients in the frontline setting were not as effective as what we use today. Over the past two decades, as those induction regimens have improved, the complete remission rates have gotten higher and the duration of initial remissions have gotten longer. That has led many in the field to question whether the continued use of autologous transplant in first remission for patients with mantle cell lymphoma was still providing benefit.
What this trial demonstrates is that, at least for those patients who achieve a minimal residual disease negative complete remission, the outcomes with respect to progression free and overall survival are equivalent for those patients without autologous transplant compared to those for patients who do receive autologous transplant. So for that subgroup of patients autologous transplant appears to show no benefit.
Those findings are consistent with the data that were reported from the TRIANGLE trial which was a three-arm randomised controlled trial that similarly evaluated the impact of adding a novel agent, ibrutinib, to standard chemotherapy followed by transplant. What that study demonstrated is that patients who received ibrutinib, a covalent Bruton’s tyrosine kinase inhibitor, in addition to frontline chemotherapy and transplant did better than patients who underwent chemotherapy and transplant without the Bruton’s tyrosine kinase inhibitor. Importantly, the third arm of that trial demonstrated that patients who received chemotherapy and ibrutinib without transplant did just as well as patients who had a transplant when they also received ibrutinib, suggesting that for those patients receiving a BTK inhibitor up front can negate the potential advantage of high-dose chemotherapy and a transplant.
So we’ve got two sets of data here that point to the potential lack of benefit for high dose chemotherapy and autologous transplant in patients with up front treatment for mantle cell lymphoma, one showing that patients who achieve the deepest remission that we can measure with current technology with negativity of minimal residual disease doing just as well without transplant as they did with an autologous transplant, and the other trial showing that the addition of a BTK inhibitor such as ibrutinib in the frontline setting improved their outcomes, both progression free and overall survival, and that there is no incremental benefit of an autologous transplant when ibrutinib was added.
What we don’t know from the EA4151 trial is we don’t have data telling us for certain that for patients who fail to achieve complete remission that we should stop doing transplant in that setting. As part of the data that were presented on the trial at the recent ASH meeting, it was shown that patients who achieved less than a complete response to their frontline induction therapy or who still had detectable minimal residual disease had a proportion of them convert to MRD negative status following high-dose chemotherapy and autologous transplantation. Their outcomes for that subgroup of patients appeared to be as good as the outcomes for patients who were MRD negative after their initial therapy without a transplant.
What would be helpful would be to know from the TRIANGLE trial whether MRD status at the end of induction therapy predicted outcomes beyond whether or not patients received a BTK inhibitor. In that trial, MRD assessments were performed as exploratory endpoints but those data have not yet been analysed and reported. So we’re waiting to learn about that.
What we can conclude from the evidence from both trials combined is that the majority of patients with mantle cell lymphoma whom we have historically treated with intensive frontline therapy, including high-dose chemotherapy and autologous transplant, are likely to do just as well without a transplant, either if they are documented to be in an MRD negative remission at the end of their induction therapy or if they receive a BTK inhibitor as part of their initial induction course and maintenance therapy, which is the pattern in which it was administered in the TRIANGLE trial. Our own practice since the reporting of these two studies has shifted in that direction where we are now no longer recommending consolidation with an autologous transplant in the frontline setting and we are incorporating a covalent BTK inhibitor into both the induction and maintenance phases of their treatment.
