Ibrutinib Added to ASCT Shows Promise as a First-Line Treatment Option for MCL

Martin Dreyling, MD

The addition of ibrutinib (Imbruvica) to standard chemoimmunotherapy induction followed by autologous stem cell transplantation (ASCT) and 2 years of maintenance ibrutinib can improve outcomes compared with standard chemoimmunotherapy induction and ASCT alone for younger patients with mantle cell lymphoma (MCL), according to findings from the phase 3 TRIANGLE study (NCT02858258).

Results of the study were presented by Martin Dreyling, MD, at the 2022 American Society of Hematology (ASH) Annual Meeting.

A total of 870 patients were enrolled and randomized in the trial between July 2016 and December 2020 to receive either the previous standard treatment (n = 288), the addition of ibrutinib to standard treatment (n = 292), or ibrutinib without ASCT (n = 290). Among those enrolled, the median age was 57 years (range, 27-68), with 76% of the patients being male, and 87% with stage IV disease.

The overall response and complete response rates were 94% and 36% for the 272 evaluable patients in the arm with standard treatment vs 98% and 45% for the 559 evaluable patients in the other 2 arms.

For the primary end point of the 3-arm study, failure-free survival (FFS), the 3-year FFS rate was 72% with standard induction and ASCT vs 88% with ibrutinib plus induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; P = .0008). Treatment with standard chemoimmunotherapy induction and ASCT did not elicit superior FFS vs ibrutinib and chemoimmunotherapy as induction and 2-years of ibrutinib maintenance without ASCT.

Further, grade 3-5 adverse events were similar between the chemoimmunotherapy induction groups following induction therapy with the most frequent in patients receiving chemoimmunotherapy alone vs the addition of ibrutinib for maintenance including thrombocytopenia (59% vs 61%) neutropenia (47% vs 49%), anemia (22% vs 24%), leukopenia (15% in both), febrile neutropenia (9% vs 12%), infections/infestations (9% vs 12%), and cardiac disorders (2% vs 3%). In the first arm with standard therapy, there were 3 grade 5 events observed compared with 2 in ibrutinib-containing arms.

In an interview with Targeted Oncology^TM, Dreyling, Department of Internal Medicine III, LMU University Hospital Munich, in Germany, discussed the implications of the findings from the TRIANGLE study in patients with MCL.

Can you discuss ibrutinib and its role as a BTK inhibitor?

Dreyling: Ibrutinib is the first run of the Bruton’s tyrosine kinase inhibitors [BTKis]. The Bruton’s tyrosine kinase is a signal pathway downstream of the B-cell receptor. The B-cell receptor is somewhat the survival signal of the normal lymphocytes when it gets to the general center. What does the malignant cell want to do? It wants to survive. Therefore, malignant diseases, including chronic lymphocytic leukemia and mantle cell lymphoma, have turned on this point and therefore, it's a very attractive target for targeted therapy with BTKi.

What sets ibrutinib apart from other BTK-inhibitors?

It's the first in a row of BTKi. When it was introduced into medicine, which was already quite a while ago, it was a standalone approach. Meanwhile, we have a second generation of BTKi. When it comes to efficacy, they're quite similar but with toxicity, there is a slight difference there. [It is] a little bit better tolerated, so as a rule of thumb, the follow-up compounds have [about] 50% less toxicity.

Can you discuss the background of the TRIANGLE study?

In younger patients with mantle cell lymphoma, we established the standard of autologous transplant about 20 years ago based on a randomized trial. This year, we were able to present our data on the TRIANGLE trial and that was comparing the old standard to either an add on design, which means autologous transplant plus ibrutinib or ibrutinib alone. Autologous transplant is sufficient, but it also [comes with] toxicity, which goes with high-dose chemotherapy. Therefore, everyone tries to get rid of it.

What were the results from the study?

In this study, a huge study with almost 900 patients, we could show that first, the add on ARM A plus I, autologous transplant plus ibrutinib, did result not only in a statistically significant but also a clinically meaningful improvement of progression-free survival [PFS]. So, after 3 years, it's in the range of 15%.

The second comparison is autologous vs ibrutinib, interestingly. The predefined statistical question was superiority of autologous transplant. It's only worthwhile, the additional toxicity if it's significantly worse. To our surprise, the curves are flipping, and therefore the ibrutinib arm is again about 50% improved PFS better after 3 years than the autologous transplant arm.

The third question, we don't know yet. If you take ibrutinib for granted, what about additional autologous transplant? But what we have seen is that the combination, maybe not totally unexpected, has an increased toxicity. Therefore, the data as they now are clear that the autologous standalone arm is no longer the standard of care and that the ibrutinib alone arm is the best tolerated one.

Overall survival is also improved by about 5%, which is quite encouraging for both ibrutinib-containing arms. Secondly, the kind of patients which are hard to treat, these are the ones with p53 mutations, they have an excellent outcome now with the addition of ibrutinib. To sum up, the lifecycle of autologous transplant in mantle cell lymphoma is over and I am quite confident that this treatment will be included in both the United States guidelines as well as the international ones.

What are the next steps for this trial?

I think the next steps will be inclusion in the guidelines [and] as we now have proven, get rid of part of the chemotherapy. What about getting rid of chemotherapy overall, and therefore, this is our next step. We will activate 2 randomized trials during the next 6 months or so and both will be randomized trials between the new standard which is chemo plus ibrutinib vs a non-chemo arm. These results will be interesting, but that's to be reported in 3 to 4 years from now.

REFERENCE:

Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized triangle trial by the European MCL network.Presented at: 2022 ASH Annual Meeting; December 10-13, 2022; New Orleans, LA. Abstract 1