TRIANGLE Study: Ibrutinib vs Stem Cell Transplant in Younger Patients With MCL


Boyu Hu, MD, and Bijal D. Shah, MD, provide their thoughts on the TRIANGLE study looking at ibrutinib versus stem cell transplant in MCL.


Alexey V. Danilov, MD, PhD: BTK [bruton tyrosine kinase] inhibitors completely changed the treatment landscape of mantle cell lymphoma [MCL] in the past 5 or 7 years. BTK inhibition has been one of the most significant advances in lymphoma therapy. BTK inhibition is based on recognition of the fact that microenvironment is critically important in maintenance of survival of mantle cell lymphoma cells. The signals which emanate from the microenvironment are transmitted through the B-cell receptor, and BTK is a key kinase which is indispensable for B-cell receptor signaling. Blocking this kinase with BTK inhibitors results in abrogation of survival of lymphoma cells.

Now, we have many studies which have introduced BTK inhibitors into practice in mantle cell lymphoma, and we have even more studies now which moved the needle in terms of how we are going to use BTK inhibitors 3 or 5 years from now. One such study—the TRIANGLE study—was presented at the most recent ASH [American Society of Hematology] annual meeting. Boyu, would you please tell us about it?

Boyu Hu, MD: Yes. The TRIANGLE study [NCT02858258] was one of the plenary sessions at this year’s ASH [meeting]. It was a large, randomized phase 3 trial conducted in Europe and at other affiliate sites that essentially recruited young autologous stem cell transplant-eligible patients and [those] who could also receive cytarabine. It was a 3-arm study. The standard of care was chemotherapy with a cytarabine-based regimen followed by autologous stem cell transplant. The second arm was chemotherapy plus ibrutinib followed by autologous stem cell transplant and ibrutinib maintenance for 2 years. The third arm was chemotherapy with…just ibrutinib.

[The study] was used to do 2 things. One was to try to figure out whether the addition of ibrutinib to frontline chemotherapy could improve outcomes and whether the ibrutinib maintenance or the addition of ibrutinib to frontline and also maintenance could get rid of autologous stem cell transplant altogether. After 750 patients [were] accrued, the addition of ibrutinib did make a big difference in that. We did see better outcomes with the patients treated with ibrutinib added to frontline therapy and, also, in the maintenance setting. In fact, the patients who didn’t receive autologous stem cell transplant did just as well or even better than the standard-of-care arm, which was chemotherapy [then an autologous stem cell transplant].

I will say that this study’s going to be up for debate for quite a long time, whether there’s any clinical significance. There were some things that I think were missing from the study, including stratification of patients due to high-risk features that we know of. Blastoid pleomorphic variants and TP53 mutation were not really reported. I’m interested to see what the results look like if we take out the TP53 [tumor protein]-mutated patients from this analysis. Potentially, we know that patients with those high-risk mutations don’t do as well with chemotherapy alone and, most likely, the addition of a novel therapy like a BTK inhibitor does improve their outcomes.

Alexey V. Danilov, MD, PhD: Thank you, Boyu. Bijal, is this trial practice-changing from your perspective?

Bijal D. Shah, MD: Ding dong, the transplant is dead. It’s amazing that we have a randomized trial. You’re right, we’re going to pick at it, and we’re going to try to understand whether the transplant does benefit a subset of patients. This isn’t the first negative transplant study. The previous study looking at CHOP [cyclophosphamide/doxorubicin/vincristine/prednisone], later amended to R-CHOP [rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone] followed by autologous stem cell transplant was also a negative study when it came to survival. This is what matters. We didn’t improve survival in all comers with mantle cell lymphoma using R-CHOP again, as the induction approach. We have to finally acknowledge and accept that it may not be the best approach, but again, I’m a biased person. I’m allowed to have my biases. It is OK for others to say…it provides a platform for extending that failure-free survival.

What I love about this trial is you can nitpick about how much the transplant adds or doesn’t add. The failure-free survival in all 3 arms was outstanding. If it’s me treating my patients who tend to be a lot more like your patients presenting in their mid to late 70s, I’m not going to be excited about transplant. I’m going to be much more excited about now bringing BTKs forward.

Alexey V. Danilov, MD, PhD: What do you think, Matt?

Matthew J. Matasar, MD: I’m not quite as militant, but what else is new? What I would say is that I agree with you, Bijal. It’s encouraging that we can now say with greater confidence that not everybody who’s young and fit needs to get an auto consolidation. We’ve already known that. [In] P53 patients, we haven’t been doing that anyway. It’s clear to me that TRIANGLE is going to further reduce my need to offer first-line auto consolidation for young, fit patients with mantle cell lymphoma. I do want to pick it apart a bit because I don’t think that we’re going to end in a one-size-fits-all situation. I do believe that there’s some subset of patients that will emerge from a more granular look at the data that may derive some incremental benefit from the auto [consolidation], and for that patient, working through the pros and cons for them may lead to preference for more intensified first-line treatment if it buys you a longer time to next line of therapy. Who those patients are, what the risk-benefit profile is—that’s what we’re going to need to determine as a community.

Alexey V. Danilov, MD, PhD: Thank you, Matt. Certainly exciting data. We are looking forward to more follow-up, and like you said, granular data will help us decide ultimately whether the transplant is alive.

Transcript edited for clarity.

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