Adding Ibrutinib to Chemoimmunotherapy Induction Improves FFS in Younger MCL

First-line treatment with ibrutinib (Imbruvica) plus chemoimmunotherapy induction and autologous stem-cell transplantation (ASCT), followed by ibrutinib maintenance, improved efficacy vs chemoimmunotherapy induction plus ASCT alone in younger, medically fit patients with mantle cell lymphoma (MCL), according to full data from the phase 3 TRIANGLE trial (NCT02858258) published in The Lancet.¹

These findings were previously presented at the 2022 ASH Annual Meeting.²

During the trial, patients were randomly assigned to receive chemoimmunotherapy plus ASCT (group A; n = 288) ibrutinib plus chemoimmunotherapy and ASCT (group A+I; n = 292), or ibrutinib plus chemoimmunotherapy without ASCT (group I; n = 290).¹

At a median follow-up of 31 months (95% CI, 30.1–33.0), the 3-year failure-free survival (FFS) rates were 72% (95% CI, 67%-79%) for group A and 88% (95% CI, 84%-92%) for group A+I (HR, 0.52; one-sided 98.3% CI, 0.00-0.86; one-sided P = .0008). This benefit was consistent across various subgroups, including MCL International Prognostic Index (MIPI) status, cytology, Ki-67 index, and rituximab (Rituxan) maintenance. Patients in group A+I experienced a significant FFS benefit if they had high p53 expression (HR, 0.14; one-sided 98·3% CI, 0.00-0.57) or high-risk biology (high combined MIPI or p53 immunohistochemistry expression of >50%; HR, 0.31; one-sided 98.3% CI, 0.00-0.78).

Additionally, the 3-year FFS rate was 72% (95%, CI, 67%-79%) for group A vs 86% (95% CI, 82%-91%) for group I (HR, 1.77; one-sided 98.3% CI, 0.00-3.76; one-sided P = .9979).

“Our phase 3 trial demonstrates the superior efficacy of ibrutinib-containing [chemoimmunotherapy] compared with the pre-trial standard approach with ASCT consolidation and defines a new standard of care in frontline treatment of young, medically fit [patients with MCL]. Whether ASCT, with additional toxicity, still adds benefit to ibrutinib-based treatment in subsets of patients is not yet determined,” lead author Martin Dreyling, MD, of the Department of Internal Medicine III at LMU University Hospital Munich in Germany, and colleagues, wrote in The Lancet.

TRIANGLE enrolled patients between 18 and 65 years of age with previously untreated, histologically confirmed MCL that was Ann Arbor stage II to IV. Patients needed to be suitable for treatment with ASCT, have a minimum of 1 measurable lesion, and have an ECOG performance status of 2 or less. Exclusion criteria included anticoagulation with warfarin or equivalent vitamin K antagonists, or treatment with strong CYP3A4 or CYP3A5 inhibitors; a history of intracranial hemorrhage within 6 months of randomization; and known central nervous system involvement.

The investigator-sponsored, multicenter, randomized, open-label, 3-arm, parallel-group, confirmatory superiority study was conducted across 165 secondary or tertiary university, community, or private hospitals and clinical centers in Europe. Patients were randomly assigned to 1:1:1 to 3 treatment groups: group A, group A+I, and group I.

A total of 907 patients were assessed for eligibility between July 29, 2016, to December 28, 2020, and 37 patients were excluded due to screening failure; 870 patients were randomly assigned to their respective treatment groups. Specifically, 288 patients were assigned to group A (2 patients did not start induction due to patient decision); 292 were assigned to group A+I; and 290 were assigned to group I (2 patients did not start induction due to patient decision). At the data cutoff date on May 22, 2022, 808 patients (group A, n = 261; group A+I, n = 275; group I, n = 272) completed 6 cycles of induction treatment.

Across all 3 groups, induction chemoimmunotherapy consisted of 6 alternating cycles of R-CHOP and either R-DHAP or R-DHAOx. R-CHOP was comprised of rituximab at 375 mg/m2 on day 0 or day 1 plus cyclophosphamide at 750 mg/m2 on day 1, doxorubicin at 50 mg/ m2 on day 1, vincristine at 1.4 mg/m2 on day 1, and oral prednisone at 100 mg on days 1 through 5. R-DHAP featured rituximab at 375 mg/m2 on day 0 or 1 plus dexamethasone at 40 mg on days 1 to 4, intravenous cytarabine at 2 × 2 g/m2 for 3 hours every 12 hours on day 2, and cisplatin at 100 mg/m2 on day 1. R-DHAOx featured rituximab at 375 mg/m2 on day 0 or 1, dexamethasone at 40 mg on days 1 through 4, cytarabine at 2 × 2 g/m2 for 3 hours every 12 hours on day 2, and oxaliplatin at 130 mg/m2 on day 1.

Patients in group A+I and I also received oral ibrutinib at 560 mg on days 1 through 19 of R-CHOP cycles. Patients who did not experience an FFS event after induction received continuous ibrutinib at 560 mg daily for 2 years as maintenance therapy.

For patients in groups A and A+I, ASCT was performed using THAM conditioning, which consisted of total body irradiation at 10 Gy on days –7 to –5, cytarabine at 1.5 g/m2 twice daily on days –4 and –3, and melphalan at 140 mg/m2 over 1 hour on day –2; or BEAM/TEAM comprised of carmustine at 300 mg/m2 over 1 hour on day –7 or thiotepa at 5 mg/kg twice daily on day –7; etoposide at 2 × 100 mg/m2 over 1 hour every 12 hours on day –6 to –3; cytarabine at 2 × 200 mg/m2 over 30 minutes every 12 hours on day –6 to –3; and melphalan at 140 mg/m2 over 1 hour on day –2. These regimens were chosen at the investigator's discretion.

In all study groups, 3 years of rituximab maintenance could be added per national guidelines.

The primary end point of the study was investigator-assessed FFS, which was defined as either time from randomization to stable disease at the end of induction immunochemotherapy, progressive disease, or death from any cause on the trial—whichever occurred first. Secondary end points include overall survival (OS), progression-free survival (PFS), duration of remission

(DOR), complete remission (CR) rates, rate of conversion from partial remission (PR) to CR following induction, and safety.

Regarding patient characteristics, the median age in group A was 57 years (range, 52-61); the majority of patients were male (76%), White (98%), and had MCL (99%). Patients in group A had an Ann Arbor stage of II (4%), III (8%), or IV (88%), and an ECOG performance status of 0 (74%), 1 (24%), or 2 (2%). Forty-three percent of patients had a lactate dehydrogenase (LDH) level above the upper limit of normal (ULN). MIPI status included low (58%), intermediate (27%), and high (14%); the Ki-67 index was greater than 30% in 33% of patients. Additionally, 11% of patients had blastoid cytology, 11% had a P53 expression above 50%, and 17% had high-risk biology.

In group A+I, the median age was 57 years (range, 52-61), and the majority of patients were male (74%), White (97%), and had MCL (99%). Ann Arbor stage included II (4%), III (7%), or IV (89%), and ECOG performance status was 0 (73%), 1 (26%), or 2 (1%). Forty-one percent of patients had an LDH level above the ULN. MIPI status ranged from low (58%) to intermediate (27%) and high (15%); the Ki-67 index was greater than 30% in 31% of patients. Additionally, 13% of patients had blastoid cytology, 14% had a P53 expression above 50%, and 21% had high-risk biology.

Finally, in group I, the median age was 57.5 years (range, 52-61), a majority of patients were male (79%), White (100%), and had MCL (99%). Patients had an Ann Arbor stage of II (6%), III (10%), or IV (84%); ECOG performance status was 0 (72%), 1 (27%), or 2 (2%). Thirty-six percent of patients had an LDH level above the ULN. MIPI status ranged from low (58%) to intermediate (27%) and high (16%). Ki-67 index was greater than 30% in 32% of patients. Additionally, 12% of patients had blastoid cytology, 16% had a P53 expression above 50%, and 23% had high-risk biology.

ASCT was completed in 242 and 250 patients in groups A and A+I, respectively. In patients from group I, 3 patients completed ASCT, deviating from the designated study group. In group A+I, 238 patients began ibrutinib maintenance; and in group I, 260 started ibrutinib maintenance. In patients who started maintenance with the BTK inhibitor, 41% in group A+I and 32% in group I stopped ibrutinib maintenance more than 2 weeks before the completion of 2 years.

In group A+I, the median duration of ibrutinib maintenance was 22.3 months (range, 0.1-29.7; interquartile range [IQR], 7.4-24.0) and 23.9 months (range, 0.2-28.3; IQR, 15.4-24.0) for group I. The median time between the end of ASCT and start of ibrutinib maintenance was 49 days (range, 20-351; IQR, 39-75) in group A+I.In group A+I and group I, 70 and 78 patients, respectively, were still on ibrutinib maintenance by at data cutoff.

Rituximab maintenance was given to 58% of patients in group A, 57% of patients in group A+I, and 54% of patients in group I. Among 546 patients where treatment was ended (group A, n = 210; group A+I, n = 168; group I, n = 168), 340 ceased ibrutinib or rituximab treatment during maintenance (n = 69; n = 127; n = 144); 206 patients either did not start maintenance, progressed, or died during maintenance (n = 141; n = 41; n = 24).

The 3-year OS rates were 86% (95% CI, 82%-91%) in group A, 91% (95% CI, 88%-95%) in group A+I, and 92% (95% CI, 88%-95%) in group I.

The 3-year duration of remission rates were 76% (95% CI, 70%-83%) in group A, 88% (95% CI, 84%-93%) in group A+I, and 87% (95% CI, 82%-92%) in group I (HR for A+I vs A, 0.52; one-sided 98·3% CI, 0.00-0·84; P = .0021; HR for A vs I, 1.80; one-sided 98.3% CI, 0.00-2.91; P > .99).

At the end of induction, the CR rate in groups A+I and I combined was 45% (95% CI, 41%-49%) vs 36% (95% CI, 30%-42%) for group A (P = .020). The overall response rate was 98% (95% CI, 97%-99%) vs 94% (95% CI, 91%-97%), respectively (P = .0025). Among patients who initially experienced a PR, 62% (95% CI, 54%-70%) of patients achieved CR during follow-up in group A, vs 66% (95% CI, 58%-74%) in group A+I and 57% (95% CI, 49%-65%) in group I.

The main causes of death were progressive lymphoma (group A, 6%; group A+I, 1%; group I, 4%) and other comorbidities (4%; 2%; 2%). Treatment-related deaths occurred in 1% of patients in group A and 1% in group A+I, and there were no treatment-related deaths in group I.

More patients experienced disease progression or death in group A (n = 67) compared with group A+I (n = 34) or group I (n = 35). The 3-year PFS rates were 73% (95% CI, 67%-79%) for group A, 88% (95% CI, 84%-93%) for group A+I, and 87% (95% CI, 83%-92%) for group I (HR for A+I vs A, 0.46; one-sided 98.3% CI, 0.00-0.72; one-sided P = .0001; HR for A vs I, 2.10; 95% CI, 0.00-3.28; P > .99).

During the induction of treatment, the most common grade 3 to 5 adverse effects (AEs) were related to blood and lymphatic system disorders, occurring in 71% of the patients treated with R-CHOP/R-DHAP and 76% of those treated with IR-CHOP/R-DHAP. These included decreased platelets (R-CHOP/R-DHAP, 59%; IR-CHOP/R-DHAP, 61%), decreased neutrophil count (47%; 50%), and anemia (22%; 24). During ASCT, blood and lymphatic system disorders were the primary grade 3 to 5 AEs, affecting 59% of 245 patients in the R-CHOP/R-DHAP group and 159% of the 254 patients in the IR-CHOP/R-DHAP group. Other grade 3 to 5 AEs during ASCT included general disorders and administration site conditions (R-CHOP/R-DHAP, 20%; IR-CHOP/R-DHAP, 21%); gastrointestinal disorders (21%; 20%); and infections (17%; 20%).

During maintenance or follow-up, more grade 3 to 5 AEs were reported in group A+I and group I compared with group A. Blood and lymphatic system disorders were observed in 50% of patients in group A+I (n = 231), 28% of group I (n = 269), and 21% of group A (n = 238), with decreased neutrophil count being the most common (44%; 23%; 17%). Infections were reported in 25% of patients in group A+I, 19% of patients in group I, and 13% of patients in group A. Furthermore, infections were the most common fatal AE during ASCT (group A+I, 2%; group A, 2%) and during maintenance or follow-up (group A+I, 1%; group I, 1%; group A, 1%).

References

1. Dreyling M, Doorduijn J, Giné 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. Lancet. Published online May 2, 2024. doi:10.1016/ S0140-6736(24)00184-3
2. 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. Blood. 2022;140(suppl 1):1-3. doi:10.1182/blood-2022-163018