The End of Transplant for Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) has been called “the worst of both worlds” because patients both have an aggressive clinical course and almost invariably relapse. Over the years, historically short overall survival (OS) of patients with MCL has led to concerted efforts to improve outcomes with intensive therapy. A prospective trial published in 2005 showed that high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improved progression-free survival (PFS), leading to frequent adoption of this practice.¹  Subsequently, however, improved induction regimens such as bendamustine plus rituximab were introduced, as was the addition of rituximab maintenance treatment, which improves outcomes in MCL patients regardless of ASCT.^2-4  Further improvements have come from salvage strategies including oral Bruton tyrosine kinase (BTK) inhibitors, as well as CD19-directed chimeric antigen receptor T-cell therapy. The shifting treatment landscape has led to significant interest in exploring whether the morbidity, toxicity, and potential late effects of ASCT continue to be justified in the modern era.

The Triangle study was a large prospective three-arm clinical trial conducted at multiple European sites.¹  A total of 870 patients responding to intensive induction treatment were randomized to undergo ASCT alone, ASCT with ibrutinib during and after transplant, or ibrutinib without ASCT. While rituximab maintenance was not required, it was administered to 59 to 67% of the study participants.⁵  Patients treated with ibrutinib without ASCT had superior outcomes relative to those who received ASCT alone, with a three-year failure-free survival of 86% versus 75% (p=0.003) and a three-year OS of 91% versus 85% (p=0.004).⁶  Due to these findings, National Comprehensive Cancer Network guidelines have adopted the provision of BTK inhibitors in combination with maintenance rituximab as an alternative to ASCT.

Additional compelling data demonstrating that ASCT is not beneficial for most MCL patients was presented at the 2024 ASH annual meeting in a late-breaking abstract. The E4151 trial was a four-arm trial conducted through the National Cancer Institute’s National Clinical Trials Network and the Blood and Marrow Transplant Clinical Trials Network.⁷  A total of 650 patients in complete remission after induction chemoimmunotherapy who had undetectable MRD at 1 in 10^-6 sensitivity were randomized to either ASCT plus three years of maintenance rituximab or three years of maintenance rituximab alone. There was no difference in three-year PFS (77% vs. 77%) or OS (82% vs. 83%) between these arms. The outcomes of a relatively small number of patients who were either MRD-positive (MRD+) or MRD-indeterminate who received ASCT were similar to those who were MRD negative prior to ASCT. About half of the MRD+ patients converted to undetectable MRD after ASCT and had three-year PFS and OS of 100%, while those who remained MRD+ had much worse outcomes.

What are the implications of these two highly important and well-conducted prospective clinical trials? Taken together, Triangle and EA4151 are practice changing. EA4151 shows that in the absence of BTK inhibitor therapy, rituximab maintenance effectively compensates for the omission of ASCT for patients in deep remission. Furthermore, Triangle demonstrated that OS is improved by replacing ASCT with BTK inhibitor therapy. Will the oncology community adjust practice? There has already been a decline in the total number of patients receiving ASCT for MCL, and it would be reasonable to anticipate further diminution of this practice (Figure). The benefit will be fewer patients receiving intensive and toxic treatment with known late effects, including secondary malignancies. Looking forward, additional studies will be needed to explore whether all patients require BTK inhibitor therapy or if rituximab maintenance alone may be adequate in some cases (based on MRD status, for instance). These questions will likely be answered in the future, but for now, it is time to transplant old practice in favor of new treatment approaches for MCL.