What is your outlook on the role of upfront autologous stem cell transplant (ASCT) for patients with mantle cell lymphoma (MCL)?
Dr. Barrientos: Most of the data that we have for upfront ASCT for young patients in frontline therapy come from the era when we did not use rituximab, and the data have not kept up with the pace of all the recent advances. Rituximab has changed the way we approach maintenance therapy after induction therapy. No randomized controlled trial data (in regimens that incorporate rituximab and cytarabine) have demonstrated a benefit in overall survival (OS) with ASCT in the modern era.
There is a lot to consider for every patient with MCL before we start therapy or discuss upfront transplant. MCL is one of these non-Hodgkin lymphomas that unfortunately can be aggressive in some patients depending on their prognostic markers and particular clinical features of the disease. Some patients have a more indolent form, whereas others have a more aggressive presentation at the time of diagnosis. The disease is heterogeneous and will respond differently to certain regimens. For example, patients with MCL who have a high proliferation rate, blastoid morphology, multiple chromosomal aberrations, complex karyotype, and/or the presence of tumor suppressor protein P53 (TP53) mutation will likely have a more aggressive course. Fitness for transplant is also an important consideration regardless of age; that is, a patient with comorbid end-stage chronic kidney or liver disease will not be able to tolerate a transplant.
Even with optimal therapy that incorporates rituximab and cytarabine, pursuing a transplant does not necessarily benefit survival in patients with a known TP53 mutation, as these patients typically experience increased toxicity without improved OS. We know they will not respond well, and we should discuss the available data so that the patients can make a sound decision and consider participation in a clinical trial that incorporates novel agents. Another type of mutation—cyclin-dependent kinase inhibitor 2A (CDKN2A)—also has lower OS. Concurrent deletion of CDKN2A and TP53 aberration (deletion and/or mutation) are known to be associated with lower OS given their chemoresistant nature. Patients with these genetic mutations should not be offered standard ASCT, but rather they should be identified early on and prioritized to participate in clinical trials.
Importantly, the role of upfront ASCT is changing right now, based on a recent trial that was presented at the latest American Society of Hematology meeting in 2022. The TRIANGLE trial demonstrated the addition of ibrutinib (a first-generation Bruton tyrosine kinase [BTK] inhibitor) to standard chemoimmunotherapy induction and 2 years of ibrutinib maintenance can improve outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL. However, longer follow-up is needed to fully elucidate the role of ASCT in the era of BTK inhibitors when incorporated early on into the treatment paradigm.
The TRIANGLE trial was an international, randomized 3-arm phase 3 trial (EudraCT-no. 2014-001363-12) for young (up to 65 years) fit patients with histologically confirmed, untreated, advanced stage II-IV MCL. In the control arm A, patients received an alternating R-CHOP/R-DHAP induction followed by myeloablative consolidation (ASCT). In arm A+I, ibrutinib was added to the R-CHOP cycles (560 mg day 1-19) and was applied as maintenance (continuous dosing) for 2 years. In arm I, the same induction and maintenance was applied but high-dose consolidation and ASCT was skipped. A rituximab maintenance (single doses every 2 months for up to 3 years) was allowed to be added in all study arms according to national clinical routine.