Addition of ASCT to Ibrutinib Plus Rituximab Does Not Confer Benefit in Lower-Risk, Younger MCL

The addition of autologous stem cell transplantation (ASCT) to ibrutinib (Imbruvica) plus rituximab (Rituxan) and chemotherapy did not produce efficacy or safety benefits compared with ibrutinib plus rituximab and chemotherapy without ASCT in patients with mantle cell lymphoma (MCL) younger than 65 years of age, according to data from the phase 3 TRIANGLE trial (NCT02858258) presented at the 2024 ASH Annual Meeting.

“We presented the first data [from TRIANGLE in 2022], and those were published in The Lancet in 2024, but there was criticism,” Martin Dreyling, MD, PhD, said during an interview with OncLive®. “These are well-taken criticism points. One point was that the [initial median] follow-up was rather short, only [31 months], which is too short for a first-line study. The second point was that, at the time, we were not yet able to provide meaningful data on overall survival [OS].”

In TRIANGLE, investigators randomly assigned patients 1:1:1 to receive chemotherapy plus rituximab followed by ASCT (arm A; n = 288); chemotherapy plus rituximab and ibrutinib followed by ASCT (arm A + I; n = 292); or chemotherapy, rituximab, and ibrutinib without ASCT (arm I; n = 290).1 Data previously published in The Lancet showed that after a median follow-up of 31 months (95% CI, 30.1%-33.0%), the failure-free survival (FFS) outcomes with the arm A + I regimen were superior to those with the arm A regimen, generating a 3-year FFS rate of 88% (95% CI, 84%-92%) vs 72% (95% CI, 67%-79%; HR, 0.52 [1-sided 98.3% CI, 0.00-0.86; 1-sided P = .0008]). Additionally, the 3-year FFS rate in arm A was not superior to the 86% (95% CI, 82%-91%) FFS rate observed in arm I (HR, 1.77; 1-sided 98.3% CI, 0.00-3.76; 1-sided P = .9979).

Findings presented at the 2024 ASH Annual Meeting demonstrated that at a median follow-up of 55 months, 4-year FFS outcomes were superior in arm A + I vs arm A, with respective 4-year FFS rates of 82% and 70% (HR, 0.64; 1-sided P = .0026).2 Furthermore, 4-year FFS outcomes were not superior in arm A vs arm I, nor in arm A + I vs arm I. The 4-year FFS rates in arms A and I were 70% and 81%, respectively (HR, 1.29; 1-sided P = .9890). These rates in arms A + I vs I were 82% and 81%, respectively (HR, 0.83; 1-sided P = .21).

In the interview, Dreyling discussed the TRIANGLE trial design, key efficacy data presented at the 2024 ASH Annual Meeting, safety observations, and advice to oncologists regarding the study findings.

Dreyling is a full professor in the Department of Medicine at the University Hospital LMU Munich in Germany.

OncLive: What was the design of the TRIANGLE trial?

Dreyling: We [study investigators] couldn’t agree on 1 experimental arm. We came up with the TRIANGLE design with 3 study arms, and that significantly increased the size of our study. It includes 870 patients with [MCL], a rare disease. When we started this study, I was a bit afraid of whether we would complete it. With the support of my colleagues in now 14 European countries, we completed the study. The primary study aim was FFS, with toxicity and OS being secondary study aims.

What were the key efficacy findings presented at the 2024 ASH Annual Meeting?

In the 2024 ASH presentation, we [addressed all the key end points]. Regarding the primary study aim, the FFS benefit of both experimental arms remained statistically significant and ongoing throughout the observation period. We could also prove that OS was significantly improved [in the experimental arms vs arm A].

Finally, [we found that] rituximab maintenance was independently effective. Regardless of whether patients received ibrutinib, rituximab added [to the efficacy of the maintenance therapy], and that means a combined maintenance [approach], including ibrutinib and rituximab, is the optimal way to treat these patients.

With ASCT, for the overall group, there was no benefit. Low-risk or conventional-risk patients [had unfavorable experiences with] ASCT because it is correlated with more toxicity. Outcomes looked slightly different in the 15% of patients with high-risk features—blastoid variants, high Ki-67 index, or [high p53 expression]. In these patients, there was still a benefit [with the addition of] ASCT. Therefore, in [patients with high-risk features, we should] individually decide whether to add ASCT.

What were the safety observations from this readout of the trial?

This is important. Patients benefited from rituximab maintenance and ibrutinib maintenance, and at least the high-risk patients [also benefited] ASCT. However, out of these 3 [treatments], ASCT is the weakest and the most toxic. [In] the subsequent 3 weeks [after transplant], it’s normal for patients to have low blood counts, and then they recover after 3 weeks.

[However, in TRIANGLE, during] follow-up, [54% of patients who received rituximab, ibrutinib, and ASCT] had myelosuppression [or other blood and lymphatic system disorders]; [this rate was approximately] twice as [high as that seen in] the other [trial arms]. [The addition of ASCT] also translated to an increased rate of infections during the 2-year follow-up period, [at 34% in arm A + I vs 26% in arm I]. Therefore, ASCT should be only applied when it must be and only in high-risk patients.

What advice do you have for oncologists regarding applying the results of the TRIANGLE trial to clinical practice?

The data are [being researched] more, as BTK inhibitors are the cornerstone of treatment in MCL. Here, we confirmed that chemotherapy plus ibrutinib—and in the United States, [ibrutinib might be switched with] second-generation BTK inhibitors like acalabrutinib [Calquence] and zanubrutinib [Brukinsa]—is [more effective] than chemotherapy alone. Now the question is: Can we still skip chemotherapy overall? That’s the next study generation.

What we’ve learned so far, also presented at the 2024 ASH Annual Meeting, is that our British colleagues could show that for the very low-risk patients, ibrutinib plus rituximab is [more effective] than standard, conventional-dose chemotherapy. However, that’s not the case for the intermediate- and high-risk patients. In the next study generation, we will explore combined targeted approaches. I’m honored to say that the European MCL network is now forming 2 randomized trials comparing the old standard, which is chemotherapy plus ibrutinib, against noncytostatic approaches.

Disclosures: Dr Dreyling reports receiving honoraria from AstraZeneca, Beigene, Gilead/Kite, Janssen, Lilly, Novartis, and F. Hoffman-La Roche Ltd.; receiving research funding from AbbVie, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Lilly, and F. Hoffman-La Roche Ltd.; and holding board of directors or advisory committee membership with AbbVie, AstraZeneca, Beigene, BMS/Celgene, Gilead/Kite, Janssen, Lilly/Loxo, Novartis, and F. Hoffman-La Roche Ltd.

References

1. Dreyling M, Doorduijn J, Gine E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomized, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. The Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3
2. Dreyling M, Doorduijn JK, Gine E, et al. Role of autologous stem cell transplantation in the context of ibrutinib-containing first-line treatment in younger patients with mantle cell lymphoma: results from the randomized Triangle trial by the European MCL Network. Blood; 2024;144(suppl 1):240. doi:10.1182/blood-2024-200735