Table of Contents
- Key Points
- Background: Why This Research Matters
- How the Study Was Conducted
- Detailed Treatment Protocols
- Key Findings: What the Study Showed
- Survival Results in Detail
- Side Effects and Safety
- Findings in High-Risk Patient Groups
- What This Means for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In a trial of 870 patients aged 18–65 with previously untreated mantle cell lymphoma, adding ibrutinib to first-line chemotherapy improved failure-free and overall survival compared with standard treatment.
- Adding a stem-cell transplant to ibrutinib-containing treatment gave no extra benefit and caused more severe blood-related side effects and infections.
- Four-year overall survival was 90% with ibrutinib without a transplant and 88% with ibrutinib plus a transplant, versus 81% with standard treatment.
- The authors recommend ibrutinib plus R-CHOP alternating with R-DHAP, followed by two years of ibrutinib maintenance, without a stem-cell transplant, for transplant-eligible patients aged 65 or younger.
- These results may not apply to older patients or those not eligible for intensive treatment; patients should discuss treatment choices with their healthcare team.
Background: Why This Research Matters
Mantle cell lymphoma is a challenging type of lymphoma (a cancer of the immune system's white blood cells). The disease course varies substantially from patient to patient, which makes treatment decisions difficult. Over the past decade, researchers have identified several biological markers that indicate a poor prognosis (likely worse outcome). These markers include blastoid morphology (cells that look very abnormal under the microscope). They also include a high Ki-67 index (a measure of how fast cancer cells are dividing). They also include TP53 alterations (changes in a gene that normally suppresses tumors).
Doctors also use the Mantle Cell Lymphoma International Prognostic Index (MIPI) to estimate how aggressive a patient's disease is likely to be. The MIPI combines several clinical factors into a risk score.
For younger patients (aged 65 years or younger) who are medically fit enough for intensive treatment, the previous standard approach involved dose-intensified chemotherapy followed by autologous stem-cell transplantation (ASCT). ASCT is a procedure in which a patient's own blood-forming stem cells are collected, stored, and then given back after high-dose chemotherapy. This approach, combined with the drug cytarabine and rituximab maintenance (ongoing treatment with rituximab), had led to improved long-term outcomes.
In relapsed disease (when the cancer comes back), Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib have shown superior efficacy compared with conventional chemotherapy. Ibrutinib is an oral medication that blocks a specific protein (BTK) that cancer cells rely on to survive and multiply.
The TRIANGLE trial was designed by the European Mantle Cell Lymphoma Network to investigate whether adding ibrutinib to first-line treatment could improve outcomes. The trial also asked whether ASCT was still necessary when ibrutinib was part of the treatment.
The first results from TRIANGLE, published previously, showed that adding ibrutinib to R-CHOP alternating with R-DHAP improved failure-free survival. This was followed by ASCT and then ibrutinib maintenance (group A + I). The comparison was with the pre-trial standard of R-CHOP alternating with R-DHAP followed by ASCT alone (group A). The results also showed that ibrutinib-containing treatment without ASCT (group I) was superior to the standard approach. However, the question of whether ASCT adds any benefit to ibrutinib-containing treatment remained open. The effects on overall survival had also not yet been formally evaluated.
This updated analysis, with an additional 2 years of follow-up (median 54.9 months), reports the final results. The researchers evaluated the effects on failure-free survival. The researchers newly estimated the effects on overall survival. The researchers answered the last remaining trial question: does ASCT add efficacy to ibrutinib-containing immunochemotherapy and maintenance?
How the Study Was Conducted
TRIANGLE is an investigator-initiated, international, randomized, open-label, phase 3, confirmatory superiority trial. "Open-label" means that both doctors and patients knew which treatment was being given. "Phase 3" means it is a large, definitive trial designed to confirm whether a treatment works. "Superiority" means the trial was designed to test whether one treatment is better than another.
The trial was sponsored by Munich University Hospital in Germany. It was conducted across 165 secondary or tertiary university hospitals, community hospitals, and private clinical centers in 13 European countries and Israel. The participating countries were Germany, Italy, the Netherlands, Spain, Sweden, Poland, Denmark, Switzerland, Norway, Czech Republic, Belgium, Israel, Portugal, and Finland.
Centers were eligible to participate if they had experience treating mantle cell lymphoma and either had the capability to perform ASCT or were associated with a center that could. The trial received ethical approval from the ethics committees of all participating centers. The lead ethics committee was the Ethics Committee of the Medical Faculty at LMU Munich (reference 659–15 fed).
Participants were eligible if they met the following criteria:
- Adults aged 18–65 years of any sex
- Histologically confirmed (proven by tissue examination), previously untreated mantle cell lymphoma
- Ann Arbor stage II–IV disease (moderate to advanced cancer spread)
- Suitable for ASCT
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less (meaning they could carry out most daily activities)
- At least one measurable lesion (tumor that could be measured)
Patients were not eligible if they:
- Required anticoagulation (blood thinning) with warfarin or equivalent vitamin K antagonists
- Needed treatment with strong CYP3A4 or CYP3A5 inhibitors (medications that affect how the body processes certain drugs)
- Had a history of intracranial hemorrhage (bleeding in the brain) within 6 months before randomization
- Had known central nervous system (CNS) involvement of mantle cell lymphoma
Between July 29, 2016, and December 28, 2020, a total of 870 patients were enrolled and randomly assigned. Of these, 662 patients (76%) were male and 208 patients (24%) were female. Patients were randomly assigned in a 1:1:1 ratio to one of three treatment groups:
- Group A (control group, n=288): Standard immunochemotherapy followed by ASCT
- Group A + I (n=292): Ibrutinib added to immunochemotherapy, followed by ASCT, then ibrutinib maintenance
- Group I (n=290): Ibrutinib added to immunochemotherapy, with ASCT omitted, then ibrutinib maintenance
Randomization was done using computer-generated random numbers with an unpredictable seed. The randomization was blocked and stratified by cooperative study groups and MIPI risk groups. This means that researchers ensured each treatment group had a similar mix of patients from different study groups and with different MIPI risk scores. Investigators initiated randomization through an electronic data capture system and could not predict which treatment a patient would receive.
Masking (blinding) of either ASCT or ibrutinib was not possible. This was because group I omitted ASCT and started maintenance earlier than the other groups, making it obvious which treatment a patient was receiving.
The median age of patients in all three groups was 57 years (interquartile range 52–61). Most patients had stage IV disease (88% in group A, 89% in group A + I, and 84% in group I). B symptoms (fever, night sweats, and weight loss) were present in 25% of group A patients, 27% of group A + I patients, and 31% of group I patients.
Regarding MIPI risk groups, approximately 58% of patients in each group were low-risk, 27% were intermediate-risk, and 14–16% were high-risk. The median Ki-67 index was 18–19% across groups. A Ki-67 index of 30% or higher was found in 33% of group A patients, 31% of group A + I patients, and 32% of group I patients. Blastoid cytology was present in 11–13% of patients. High p53 expression (greater than 50%) was found in 12–15% of patients. High-risk biology (defined as high-risk combined MIPI or high p53 expression) was present in 17–21% of patients.
Detailed Treatment Protocols
All three treatment groups received induction immunochemotherapy consisting of six alternating, 21-day cycles of R-CHOP and either R-DHAP or R-DHAOx.
The R-CHOP regimen included:
- Intravenous rituximab 375 mg/m² on day 0 or 1
- Cyclophosphamide 750 mg/m² on day 1
- Doxorubicin 50 mg/m² on day 1
- Vincristine 1.4 mg/m² on day 1 (up to a maximum of 2 mg)
- Oral prednisone 100 mg on days 1–5
The R-DHAP or R-DHAOx regimen included:
- Intravenous rituximab 375 mg/m² on day 0 or 1
- Intravenous or oral dexamethasone 40 mg on days 1–4
- High-dose intravenous cytarabine 2 × 2 g/m² for 3 hours every 12 hours on day 2
- Plus either intravenous cisplatin 100 mg/m² over 24 hours on day 1 (R-DHAP) or intravenous oxaliplatin 130 mg/m² on day 1 (R-DHAOx)
- G-CSF support: subcutaneous filgrastim 5 µg/kg daily from day 6, or one dose of pegfilgrastim 6 mg on day 6
In addition, patients in group A + I and group I received oral ibrutinib 560 mg daily on days 1–19 during R-CHOP cycles only. Ibrutinib was not added to R-DHAP cycles because this combination was considered too toxic. After completing induction and, for group A + I, after ASCT, patients in both ibrutinib groups received 2 years of continuous maintenance treatment with ibrutinib 560 mg daily. For group I patients, maintenance started after induction. For group A + I patients, maintenance started after ASCT.
For group A and group A + I, ASCT was performed after either THAM conditioning or BEAM/TEAM conditioning, at the investigator's discretion.
THAM conditioning consisted of:
- Total body irradiation 10 Gy on days –7 to –5
- Intravenous cytarabine 1.5 g/m² over 30 minutes twice daily on days –4 to –3
- Melphalan 140 mg/m² over 1 hour on day –2
BEAM or TEAM conditioning consisted of:
- Intravenous carmustine 300 mg/m² over 1 hour or thiotepa 5 mg/kg twice on day –7
- Etoposide 100 mg/m² over 1 hour every 12 hours on days –6 to –3
- Cytarabine 200 mg/m² over 30 minutes every 12 hours twice daily on days –6 to –3
- Melphalan 140 mg/m² over 1 hour on day –2
Rituximab maintenance was allowed according to national guidelines and, if given, was to be administered in all three treatment groups.
Response assessments were conducted by investigators using the Revised Response Criteria for Malignant Lymphoma. These assessments included physical examinations, pre-planned CT scans, laboratory tests, and bone marrow biopsies (mandatory if initial bone marrow infiltration was detected). PET-CT results were not considered for response evaluation. Response was assessed after four induction cycles, at the end of induction, 4–6 weeks after the end of induction, then every 6 months for 2 years, and annually thereafter until progression.
Central reference pathology laboratories evaluated histopathological markers for subgroup analyses. These markers included the Ki-67 index (less than 30% vs 30% or higher; less than 50% vs 50% or higher). They also included p53 expression (50% or less vs greater than 50%). They also included high-risk biology (defined as high-risk combined MIPI or high p53 expression).
The primary outcome was investigator-assessed failure-free survival. This was defined as the time from randomization to the first occurrence of stable disease at the end of induction immunochemotherapy, progressive disease, or death from any cause. This endpoint represents a modified form of progression-free survival that specifically includes stable disease at the end of induction as an event. Stable disease at the end of induction was considered an indication for salvage treatment at the discretion of the treating physician.
Secondary outcomes included overall survival (time from randomization to death from any cause). They included progression-free survival (time from randomization to disease progression or death). They included duration of remission (time from end of successful induction to disease progression or death). They included overall response and complete remission rates. They included the conversion rate from partial to complete remission following induction therapy.
Adverse event reporting was required from randomization until 30 days after the last trial medication was given. Adverse event documentation was not mandatory during the observation period after ASCT for patients in group A. Safety outcomes included the frequencies of grade 3–5 adverse events according to Common Terminology Criteria for Adverse Events.
Key Findings: What the Study Showed
After a median follow-up of 54.9 months (95% confidence interval 54.4–56.0), the trial produced three main findings.
First, adding ASCT to ibrutinib-containing treatment did not improve outcomes. Group A + I did not show superiority over group I. The 4-year failure-free survival rate was 82% (95% CI 78–87) in group A + I versus 81% (95% CI 76–86) in group I. The hazard ratio was 0.86 (one-sided 98.33% CI 0.00–1.27), with a one-sided p-value of 0.21. This means there was no statistically significant difference between the two groups.
Second, ibrutinib-containing treatment with ASCT remained superior to standard treatment. Group A + I was superior to group A. The 4-year failure-free survival rate was 82% (95% CI 78–87) in group A + I versus 70% (95% CI 65–76) in group A. The hazard ratio was 0.63 (one-sided 98.33% CI 0.00–0.89), with a one-sided p-value of 0.0026. This result was statistically significant.
Third, ibrutinib-containing treatment without ASCT was also superior to standard treatment. Group A did not show superiority over group I. The 4-year failure-free survival rate was 70% (95% CI 65–76) in group A versus 81% (95% CI 76–86) in group I. The hazard ratio was 1.45 (one-sided 98.33% CI 0.00–2.02), with a one-sided p-value of 0.99. This means group I was superior to group A.
Survival Results in Detail
The 4-year overall survival results showed significant improvements in both ibrutinib-containing groups compared with the standard treatment group.
- Group A + I versus Group A: 4-year overall survival was 88% (95% CI 84–92) in group A + I versus 81% (95% CI 76–85) in group A. The hazard ratio was 0.59 (95% CI 0.38–0.92), with a p-value of 0.0036. This means patients in group A + I had a 41% lower risk of death compared with group A.
- Group I versus Group A: 4-year overall survival was 90% (95% CI 87–94) in group I versus 81% (95% CI 76–85) in group A. The hazard ratio was 0.57 (95% CI 0.36–0.90), with a p-value of 0.0019. This means patients in group I had a 43% lower risk of death compared with group A.
These overall survival benefits were newly demonstrated in this updated analysis. The previous publication had only reported failure-free survival results.
Side Effects and Safety
During maintenance or follow-up, the most common grade 3–5 adverse events (severe or life-threatening side effects) were hematological disorders (blood-related problems) and infections.
Hematological disorders were reported in:
- 127 (54%) of 234 patients in group A + I
- 74 (28%) of 269 patients in group I
- 56 (23%) of 240 patients in group A
Infections were reported in:
- 80 (34%) of 234 patients in group A + I
- 71 (26%) of 269 patients in group I
- 37 (15%) of 240 patients in group A
Infections and infestations were the most common fatal adverse events during maintenance or follow-up. These occurred in four (2%) of 234 patients in group A + I and five (2%) of 269 patients in group I.
The higher rates of severe blood-related side effects and infections in group A + I compared with group I indicate increased toxicity. Adding ASCT to ibrutinib-containing treatment increased toxicity without providing additional benefit.
Findings in High-Risk Patient Groups
Preplanned subgroup analyses suggested that ASCT might potentially prolong disease control in patients with high-risk biology. High-risk biology was defined as high-risk combined MIPI or high p53 expression. However, these results were not adequately powered because the sample sizes in these subgroups were small. This means the findings are suggestive but not definitive.
The researchers note that future studies are required to clarify the potential role of ASCT in patients with biologically aggressive mantle cell lymphoma.
What This Means for Patients
This updated analysis of the TRIANGLE trial provides important information for younger patients (aged 18–65 years) with previously untreated mantle cell lymphoma who are eligible for intensive treatment.
The key message is that adding ibrutinib to first-line immunochemotherapy improves both failure-free survival and overall survival. After a median follow-up of nearly 5 years, both ibrutinib-containing groups showed relevant improvements compared with the standard treatment group.
Importantly, the addition of ASCT to an ibrutinib-containing regimen had no supplementary benefit. Patients who received ibrutinib-containing treatment without ASCT (group I) had similar failure-free survival to those who received ibrutinib-containing treatment with ASCT (group A + I). Furthermore, group I had fewer severe side effects.
The authors conclude that induction treatment with ibrutinib and R-CHOP plus R-DHAP (or R-DHAOx) should be considered as a new standard of care. This standard applies to younger patients with mantle cell lymphoma. It is followed by 2 years of maintenance treatment with ibrutinib. This regimen does not include ASCT.
For patients, this means that a treatment approach using ibrutinib plus chemotherapy, followed by ibrutinib maintenance, may offer excellent disease control without the need for a stem-cell transplant. Avoiding ASCT means avoiding the toxicity and recovery time associated with high-dose chemotherapy and stem-cell rescue.
Limitations of the Study
The trial had several limitations. First, the trial was open-label, meaning that both doctors and patients knew which treatment was being given. This could potentially influence how outcomes were assessed or reported, although the primary outcome of failure-free survival was based on objective criteria.
Second, adverse event documentation was not mandatory during the observation period after ASCT for patients in group A. This means that side effects occurring after ASCT in the control group may have been underreported.
Third, the subgroup analyses suggesting a potential benefit of ASCT in patients with high-risk biology were not adequately powered because of small sample sizes. These findings require confirmation in future studies.
Fourth, the trial included only patients aged 18–65 years who were suitable for ASCT. The results may not apply to older patients or those who are not eligible for intensive treatment.
Fifth, the trial was conducted at specialized centers with experience in mantle cell lymphoma treatment. Results may differ in other clinical settings.
Recommendations and Next Steps
Based on the results of this trial, the authors recommend the following:
- For transplant-eligible adult patients aged 65 years or younger with mantle cell lymphoma, first-line treatment should consist of ibrutinib added to R-CHOP. This is alternating with R-DHAP. It is followed by 2 years of ibrutinib maintenance without ASCT.
- Adding ASCT to ibrutinib-containing first-line treatment should not be routinely recommended because it provides no additional benefit and increases toxicity.
- Future studies are required to clarify the potential role of ASCT in patients with biologically aggressive mantle cell lymphoma, defined as high-risk combined MIPI or high p53 expression.
Patients should discuss these findings with their healthcare team when making treatment decisions. The optimal treatment approach may vary based on individual patient characteristics, disease features, and other medical conditions.
Frequently Asked Questions
Who was eligible for the TRIANGLE trial?
Patients aged 18 to 65 with previously untreated mantle cell lymphoma, stage II to IV, who could carry out most daily activities and were suitable for a stem-cell transplant. People needing certain blood thinners, strong CYP3A4 or CYP3A5 inhibitors, or with recent brain bleeding or central nervous system involvement could not take part.
What did the trial find about adding a stem-cell transplant?
Among 870 patients, adding a stem-cell transplant to ibrutinib-containing treatment gave no extra benefit. Four-year failure-free survival was 82% with the transplant versus 81% without it. The transplant group also had more severe blood-related side effects and infections, so the researchers do not routinely recommend it with this regimen.
What were the survival results with ibrutinib?
After about 4.5 years, four-year overall survival was 90% with ibrutinib plus chemotherapy without a transplant and 88% with ibrutinib plus chemotherapy plus a transplant, compared with 81% for standard treatment. This means patients receiving ibrutinib had a lower risk of death than those on standard treatment.
What side effects were reported during maintenance?
The most common severe side effects were blood-related problems and infections. Blood-related problems occurred in 54% of patients who had ibrutinib plus a transplant, 28% of those who had ibrutinib without a transplant, and 23% of those on standard treatment. Infections were the most common fatal side effect, occurring in about 2% of ibrutinib-treated patients.
What does the new recommended treatment involve?
For transplant-eligible patients aged 65 or younger, the authors recommend ibrutinib added to R-CHOP alternating with R-DHAP, followed by two years of ibrutinib maintenance, without a stem-cell transplant. This approach avoids the toxicity and recovery time linked to high-dose chemotherapy and stem-cell rescue.
Does this apply to older patients or those not fit for intensive treatment?
No. The trial only included patients aged 18 to 65 who were suitable for a stem-cell transplant. The results may not apply to older patients or those who are not eligible for intensive treatment. Patients should discuss their individual situation with their healthcare team.
I'm 57 with newly diagnosed mantle cell lymphoma and my doctor recommends chemotherapy plus a stem-cell transplant — should I get a second opinion on whether the transplant is necessary?
Yes, this is a reasonable point to seek a second opinion. In the TRIANGLE trial, adding autologous stem-cell transplantation to ibrutinib-containing treatment provided no additional benefit and caused more severe blood-related side effects and infections. Ibrutinib plus R-CHOP alternating with R-DHAP, followed by 2 years of ibrutinib maintenance without transplant, improved failure-free and overall survival in patients aged 18–65. An independent expert can review your pathology and imaging and discuss whether transplant is needed. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: 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
Authors: Martin H. Dreyling, Martin Dreyling, Jeanette K. Doorduijn, Eva Giné, Mats Jerkeman, Jan Andrzej Walewski, et al.
Publication: The Lancet, Volume 407, pages 1953–1967, May 16, 2026
Funding: Janssen
Trial registration: ClinicalTrials.gov (NCT02858258)
Note: This patient-friendly article is based on peer-reviewed research published in The Lancet. The original article is available under an Open Access CC BY 4.0 license. Copyright © 2026 The Author(s). Published by Elsevier Ltd.
