Clinical trialPhase 3Lymphoma

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, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network

Lancet · 2024870 patients (arm A: 288, arm A+I: 292, arm I: 290)

Dreyling M, Doorduijn J, Giné E, et al. Lancet. 2024. 403:2293-2306

A newer report of this study has been published: Addition of autologous stem-cell transplantation to an ibrutinib-containing first-line treatment in patients aged 18-65 years with mantle cell lymphoma (TRIANGLE): 4·5-year follow-up of a three-arm, randomised, open-label, phase 3 superiority trial of the European MCL Network (2026)

Study type: Clinical trial
Study name: TRIANGLE
Phase: Phase 3
Design: Three-arm randomised (1:1:1), open-label, superiority trial at 165 centres in 13 European countries and Israel
Sample size: 870 patients (arm A: 288, arm A+I: 292, arm I: 290)
Source: Lancet · 2024
Trial registration: NCT02858258

In plain words

Mantle cell lymphoma is a type of lymphoma that in younger patients has traditionally been treated with intensive chemotherapy followed by a stem-cell transplant using the patient's own cells. This study showed that adding ibrutinib tablets to chemotherapy and continuing them for two years controls the disease much better. Even more important, patients who took ibrutinib but did not have a transplant did at least as well as transplanted patients who did not get ibrutinib. This means that in the future many patients may be able to skip the transplant and its side effects.

Key results

88% vs 72%

3-year FFS: A+I vs A

HR 0.52 (one-sided 98.3% CI 0 to 0.86); one-sided p = 0.0008; median follow-up 31 months

72% vs 86%

3-year FFS: A vs I

Superiority of arm A (transplantation without ibrutinib) not shown; HR 1.77; one-sided p = 0.9979

Under evaluation

A+I vs I

The comparison is still ongoing

Drugs in this study:Cisplatin (Platinol)Cyclophosphamide (Endoxan)Doxorubicin (Adriamycin)Ibrutinib (Imbruvica)Oxaliplatin (Eloxatin)Rituximab (Rituxan/MabThera)

Dose and schedule cards

Ibrutinib + immunochemotherapy (TRIANGLE trial)

Previously untreated stage II–IV mantle cell lymphoma, age 18 to 65 years, eligible for autologous transplantationOn the page “Lymphoma” · Treatment regimens and dosing: mantle cell lymphoma

Previously untreated stage II–IV mantle cell lymphoma, age 18 to 65 years, eligible for autologous transplantation

Drug	Dose	Route	Schedule
R-CHOP (alternating with R-DHAP)
Rituximab	375 mg/m²	IV	Day 0 or 1
Cyclophosphamide / doxorubicin	750 / 50 mg/m²	IV	Day 1
Vincristine	1.4 mg/m² (maximum 2 mg)	IV	Day 1
Prednisone	100 mg	Oral	Days 1–5
Ibrutinib	560 mg daily	Oral	Days 1–19
R-DHAP or R-DHAOx
Rituximab	375 mg/m²	IV	Day 0 or 1
Dexamethasone	40 mg	IV or oral	Days 1–4
Cytarabine	2 g/m² over 3 hours, twice, 12 hours apart	IV	Day 2
Cisplatin (or oxaliplatin 130 mg/m² in R-DHAOx)	100 mg/m² over 24 hours	IV	Day 1
Maintenance
Ibrutinib	560 mg daily	Oral	Continuously for 2 years

Cycle length: Every 21 days (6 alternating cycles)
Duration: 6 cycles, then with or without autologous transplantation, and 2 years of ibrutinib maintenance; rituximab maintenance was permitted according to national guidelines

Doses from the TRIANGLE abstract (4.5-year follow-up). Adding transplantation to the ibrutinib-containing regimen increased grade 3–5 haematologic toxicity and infections during maintenance.

On the page “Lymphoma” · Treatment regimens and dosing: mantle cell lymphoma

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Arm A (control): R-CHOP/R-DHAP + ASCT

Six alternating cycles of R-CHOP (rituximab 375 mg/m² day 0 or 1, cyclophosphamide 750 mg/m² day 1, doxorubicin 50 mg/m² day 1, vincristine 1.4 mg/m² day 1 IV, and prednisone 100 mg orally days 1 to 5) and R-DHAP or R-DHAOx (rituximab 375 mg/m² day 0 or 1, dexamethasone 40 mg days 1 to 4, cytarabine 2 × 2 g/m² over 3 hours every 12 hours on day 2, and cisplatin 100 mg/m² over 24 hours day 1 or oxaliplatin 130 mg/m² day 1), followed by autologous transplantation.

2Arm A+I: same regimen + ibrutinib + ASCT

The arm A regimen plus ibrutinib 560 mg orally daily on days 1 to 19 of the R-CHOP cycles, and fixed-duration maintenance with ibrutinib 560 mg daily for 2 years after transplantation.

3Arm I: same regimen + ibrutinib without ASCT

Ibrutinib as in arm A+I (in induction and 2-year maintenance) but without autologous transplantation.

Source of the regimen details: Abstract of the paper (Lancet 2024), which gives the doses in full

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 to 65 years with previously untreated stage 2 to 4 mantle cell lymphoma (MCL) who were eligible for autologous stem-cell transplantation (ASCT).

Endpoints

Primary endpoint: failure-free survival (FFS), tested with three pairwise one-sided log-rank tests.

Secondary endpoints: progression-free survival, overall survival, response and safety.

Safety and side effects

During induction or transplantation, there was no important difference in grade 3 to 5 adverse events between arms. During maintenance and follow-up, grade 3 to 5 haematological adverse events and infections were more frequent after transplantation combined with ibrutinib (arm A+I: haematological 50%, infections 25%, fatal infections 1%) than with ibrutinib without transplantation (arm I: 28%, 19%, 1%) or transplantation without ibrutinib (arm A: 21%, 13%, 1%).

Clinical significance and place in guidelines

TRIANGLE challenged the role of autologous transplantation in younger patients with mantle cell lymphoma. Many centres and European guidelines now recommend adding a BTK inhibitor to induction and maintenance and consider omitting transplantation in patients receiving ibrutinib an acceptable option. Note: ibrutinib currently has no US approval for MCL (the MCL indication was voluntarily withdrawn from the US market in 2023), and its first-line use is off-label in many countries.

Limitations

The study was open-label, and follow-up (median 31 months) is short for a disease with a long course such as MCL. The key comparison A+I versus I (whether transplantation is needed in the presence of ibrutinib) was not yet complete in this report. Only patients aged 65 years or younger were enrolled.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.