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

Dreyling

"BTK inhibitors are the cornerstone of treatment in mantle cell lymphoma [MCL]. Now, where [do] we go from here? The [TRIANGLE] study [data showed] that the addition of chemotherapy plus ibrutinib—in the United States, it’s likely the second-generation BTK inhibitors like acalabrutinib and zanubrutinib—is better than chemotherapy alone [in frontline MCL]. Now the question is if we can skip chemotherapy overall? That’s the next study generation.”

Martin Dreyling, MD, full professor in the Department of Medicine at University Hospital LMU Munich, discussed the expanding role of BTK inhibitors in the treatment of mantle cell lymphoma (MCL) and the potential for chemotherapy-free regimens to redefine future therapeutic approaches in the frontline setting.

BTK inhibitors have emerged as a cornerstone in the management of MCL, and updated data have supported their integration into frontline strategies, Dreyling said. Although the combination of BTK inhibitors such as ibrutinib (Imbruvica) with chemotherapy has demonstrated improved outcomes compared with chemotherapy alone, current research efforts are increasingly focused on the potential to omit cytotoxic agents entirely. This shift reflects a growing interest in non-cytostatic, targeted strategies for select patient populations.

The European MCL Network is initiating 2 randomized clinical trials to further investigate the comparative effectiveness of chemoimmunotherapy plus a BTK inhibitor vs fully targeted, chemotherapy-free regimens. These trials aim to determine whether non-cytotoxic combinations could deliver durable disease control with minimal toxicity, particularly for biologically favorable MCL subsets.

Dreyling emphasized that the next generation of MCL trials will be critical in refining risk-adapted strategies and identifying patients who may safely forgo chemotherapy. These studies are expected to inform a new standard of care by exploring the feasibility and efficacy of fully targeted treatment platforms in MCL.

Videos

Martin Dreyling, MD, discusses the expanding role of BTK inhibitors in the treatment of mantle cell lymphoma.

Dr Dreyling on the Expanding Role of BTK Inhibitors in the Treatment of MCL

Martin Dreyling, MD

"We examined the most effective salvage treatments for relapsed mantle cell lymphoma and, based on a nonrandomized data set, identified BTK inhibitors (BTKis) as the most potent approach. Consequently, we incorporated BTKis into first-line treatment, comparing the traditional standard of care—including ASCT—with two experimental arms."

Martin Dreyling, MD, full professor in the Department of Medicine at the University Hospital LMU Munich, discusses the rationale for the randomized phase 3 TRIANGLE trial (NCT02858258), which evaluated the role of ibrutinib (Imbruvica) in combination with chemotherapy and rituximab (Rituxan) with or without autologous stem cell transplant (ASCT) vs chemoimmunotherapy and ASCT alone for in previously untreated patients with mantle cell lymphoma (MCL).

The study aimed to determine whether incorporating ibrutinib into first-line therapy could improve outcomes compared with the conventional approach of induction chemotherapy followed by ASCT and rituximab maintenance. Investigators sought to assess whether ibrutinib could enhance treatment efficacy when added to ASCT or potentially replace ASCT altogether. The trial included three arms: standard induction chemotherapy with ASCT and rituximab maintenance (arm A); induction chemotherapy plus ibrutinib followed by ASCT and rituximab maintenance (arm A+I); and a novel regimen of chemotherapy plus ibrutinib without ASCT (arm I).

The rationale for the trial was based on evidence supporting the role of cytarabine-based induction and rituximab maintenance in improving long-term disease control, Dreyling explains. Additionally, ibrutinib had previously demonstrated efficacy in relapsed/refractory MCL, prompting investigation into its integration into first-line therapy. TRIANGLE aimed to establish whether an ibrutinib-containing regimen could offer comparable or superior efficacy while reducing the treatment burden associated with ASCT.

By comparing these strategies, the trial sought to clarify whether ASCT remains necessary in the era of targeted therapy, particularly for patients who might achieve durable remissions with chemotherapy, rituximab, and ibrutinib alone.

Martin Dreyling, MD, discusses the rationale for evaluating the addtion of ibrutinib to chemoimmunotherapy and ASCT in mantle cell lymphoma.

Dr Dreyling on the Rationale Behind the TRIANGLE Study in MCL

Dr Dreyling on Safety Data With ASCT Plus Ibrutinib and Rituximab in Lower-Risk, Younger MCL

“[In TRIANGLE, during] follow-up, [54% of patients who received rituximab, ibrutinib, and ASCT] had myelosuppression [or other blood and lymphatic system disorders]. [The addition of ASCT] also translated to an increased rate of infections during the 2-year follow-up period. Therefore, ASCT should be only applied when it must be and only in high-risk patients.”

Martin Dreyling, MD, full professor, Department of Medicine, University Hospital LMU Munich, discusses updated safety results from the randomized phase 3 TRIANGLE trial (NCT02858258), which evaluated the addition of autologous stem cell transplantation (ASCT) to ibrutinib (Imbruvica) plus chemotherapy and rituximab (Rituxan) maintenance in the first-line setting for younger patients with mantle cell lymphoma (MCL).

 showed that at a median follow-up of 55 months, treatment with chemotherapy and rituximab plus ASCT (arm A; n = 288) did not result in superior failure-free survival (FFS) compared with chemotherapy, rituximab, and ibrutinib without ASCT (arm I; n = 290). However, the addition of ASCT to chemotherapy, rituximab, and ibrutinib (arm A+I; n = 292) did not significantly improve FFS over arm I (4-year FFS rate, 82% vs 81%; 1-sided 

 = .21; HR, 0.83). Overall survival findings also suggested that ASCT does not provide additional survival benefit when combined with chemotherapy, rituximab, and ibrutinib.

Safety data indicate that patients, particularly those with high-risk MCL, benefited from rituximab and ibrutinib maintenance; however, out of these 3 [treatments], ASCT is associated with the highest toxicity burden, Dreyling continues. Myelosuppression and other blood and lymphatic system disorders occurred in 54% of patients in arm A+I, approximately twice the rate observed in the other trial arms, he reports. Additionally, the rate of infections during the 2-year follow-up period was higher in arm A+I (34%) compared with arm I (26%), Dreyling notes.

Given the increased toxicity associated with ASCT, the findings suggest that this approach should be reserved for high-risk patients who would derive the most benefit, Dreyling says. For many patients with MCL, the combination of chemotherapy, rituximab, and ibrutinib without ASCT may represent a less toxic and equally effective treatment strategy, he concludes.

Martin Dreyling, MD, discusses updated safety results from the randomized phase 3 TRIANGLE trial in younger patients with lower-risk MCL.

"BTK inhibitors are the cornerstone of treatment in mantle cell lymphoma [MCL]. Now, where [do] we go from here? The [TRIANGLE] study [data showed] that the addition of chemotherapy plus ibrutinib—in the United States, it’s likely the second-generation BTK inhibitors like acalabrutinib and zanubrutinib—is better than chemotherapy alone [in frontline MCL]. Now the question is if we can skip chemotherapy overall, and that’s the next study generation.”

Martin Dreyling, MD, full professor, Department of Medicine, University Hospital LMU Munich, discusses the clinical implications and future research directions for exploring chemotherapy-free frontline treatment options for patients with mantle cell lymphoma (MCL) following 

updated results from the randomized phase 3 TRIANGLE trial

TRIANGLE evaluated 3 regimens in younger patients with MCL: ibrutinib (Imbruvica) plus chemotherapy followed by autologous stem cell transplant (ASCT); ibrutinib plus chemotherapy without ASCT; and chemotherapy alone followed by ASCT. Findings presented at the 

 showed an improvement in failure-free survival (FFS) for the 2 experimental regimens vs chemotherapy alone followed by ASCT. However, the omission of ASCT following ibrutinib plus chemotherapy did not lead to worse FFS outcomes.

Dreyling explains that although chemotherapy remains a backbone for the frontline treatment of patients with MCL, ongoing research is focusing on whether chemotherapy can be omitted without compromising efficacy for certain patient populations. Prior data have suggested that patients with low-risk MCL could achieve superior outcomes with ibrutinib plus rituximab (Rituxan) vs conventional chemotherapy. However, this was not the case for patients with intermediate- and high-risk MCL, Dreyling adds.

The European MCL Network is initiating 2 new randomized trials to further evaluate chemotherapy plus a BTK inhibitor vs novel non-cytotoxic regimens, Dreyling says. The next generation of clinical trials in MCL will be crucial in helping identify potential chemotherapy-free treatment options that could further alter the MCL treatment paradigm, he concludes.

Martin Dreyling, MD, discusses ongoing trials exploring chemotherapy-free strategies in mantle cell lymphoma using BTK inhibitors.



Dr Dreyling on the Potential for Chemotherapy-Free Treatments in MCL

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Martin Dreyling, MD, full professor, Department of Medicine, University Hospital LMU Munich, discusses updated results from the randomized phase 3 TRIANGLE trial (NCT02858258) conducted by the European MCL Network. 

The study assessed the role of ASCT in the context of ibrutinib (Imbruvica)-containing first-line therapy for younger patients with mantle cell lymphoma (MCL). The analysis addressed questions regarding progression-free survival (PFS), overall survival (OS), and the post-induction roles of rituximab (Rituxan) maintenance and ASCT.

, demonstrated that 870 patients were randomly assigned to 1 of 3 treatment arms: chemotherapy plus ASCT (arm A; n = 288), chemotherapy plus ibrutinib and ASCT (A + I; n = 292), and chemotherapy plus ibrutinib without ASCT (I; n = 290). The study population had a median age of 57 years (range, 27-68), with 87% having stage IV disease and 58% classified as low risk by the Mantle Cell Lymphoma International Prognostic Index (MIPI).

At a median follow-up of 53 months, arm I demonstrated superior failure-free survival (FFS) compared with arm A (3-year FFS: 85% vs. 75%; two-sided p = 0.0102; hazard ratio [HR]: 1.38). FFS superiority of A+I over A was confirmed (3-year FFS: 86% vs. 75%; one-sided p = 0.0034; HR: 0.64), but FFS superiority of A+I over I was not established (3-year FFS: 86% vs. 85%; one-sided 

Overall survival (OS) was improved in arms I and A+I compared with arm A. The 3-year OS rates were 91% in arm I (

Safety data indicated that autologous SCT provided no benefit for the overall population and was associated with higher toxicity. For the 10% of patients with high-risk features, including blastoid variants, high Ki-67 expression, or 

mutations, autologous SCT demonstrated potential benefit.

Dreyling noted that rituximab maintenance independently improved outcomes in all arms, and combining rituximab with ibrutinib maintenance emerged as the most effective post-induction strategy.

Dreyling concludes that ibrutinib-containing regimens significantly improve outcomes in younger patients with MCL, challenging the necessity of routine autologous SCT in this population. He emphasizes that ongoing studies are essential to further refine and personalize treatment strategies for this disease, particularly in identifying subgroups that may benefit most from SCT or other targeted approaches.

Martin Dreyling, MD, discusses the role of autologous stem cell transplantation (ASCT) in the context of ibrutinib-containing first-line therapy for younger patients with MCL.

Dr Dreyling on the Role of ASCT in Ibrutinib-Containing First-Line Therapy for Younger Patients With MCL

Martin Dreyling, MD, associate professor of medicine, University of Munich, head of the Lymphoma Program in the Department of Internal Medicine III, University Hospital of Munich (LMU), in Munich, Germany, discusses the key safety data from the phase 3 TRIANGLE trial (NCT02858258) in younger patients with mantle cell lymphoma (MCL).

Investigators evaluated the addition of ibrutinib (Imbruvica) to chemoimmunotherapy induction, followed by autologous stem cell transplant (ASCT) plus 2 years of ibrutinib maintenance vs chemoimmunotherapy and ASCT alone. A third arm also evaluated ibrutinib plus chemoimmunotherapy induction without ASCT, followed by ibrutinib maintenance. Induction therapy consisted of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin).

Data from the study presented at the 2022 ASH Annual Meeting

 showed that the 3-year failure-free survival rate (FFS) was 72% with standard induction and ASCT alone compared with 88% for ibrutinib plus induction, ASCT, and ibrutinib maintenance (HR, 0.52; 

Additionally, standard chemoimmunotherapy induction and ASCT failed to show superior FFS vs ibrutinib plus chemoimmunotherapy induction and 2-years of ibrutinib maintenance without ASCT. The 3-year failure-free survival rate was 72% for chemoimmunotherapy/ASCT vs 86% with ibrutinib without ASCT (HR, 1.77; 

Because FFS and overall survival outcomes overlapped on the curves for the 2 experimental ibrutinib arms, evaluating safety was key to distinguish between the two regimens, Dreyling explains. Investigators found that the addition of ASCT to ibrutinib/chemoimmunotherapy induction and ibrutinib maintenance significantly increased toxicity, primarily for hematological adverse effects and also infections, Dreyling adds. Notably, safety data for ibrutinib induction and maintenance without ASCT was comparable to chemoimmunotherapy induction and ASCT alone, without the acute toxicity of transplantation, Dreyling continues.

Of the 3 treatment arms, the standard treatment with chemoimmunotherapy induction and ASCT alone was outperformed by both ibrutinib-containing arms, Dreyling says. Although investigators are still waiting for additional data to differentiate the 2 experimental arms, toxicity favors the ibrutinib arm without ASCT, which would represent a major shift in standard of care, Dreyling concludes.

Martin Dreyling, MD, discusses the key safety data from the phase 3 TRIANGLE trial in younger patients with mantle cell lymphoma. 

Dr. Dreyling on Key Safety Data from the TRIANGLE Trial in MCL

Martin Dreyling, MD, associate professor of medicine, University of Munich, head of the Lymphoma Program in the Department of Internal Medicine III, University Hospital of Munich (LMU), Germany, discusses key efficacy results from the phase 3 TRIANGLE study (NCT02858258) in mantle cell lymphoma (MCL).

The open-label trial evaluated the addition of ibrutinib (Imbruvica) to standard induction chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) and fixed 2-year maintenance for young patients with mantle cell lymphoma. Induction therapy consisted of R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone)/R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin).

Patients were randomly assigned to 1 of 3 treatment arms including induction/maintenance ibrutinib plus induction chemoimmunotherapy with ASCT and, ibrutinib plus induction chemoimmunotherapy and maintenance ibrutinib without ASCT, or a standard arm of induction therapy and ASCT alone.

A head-to-head comparison of all treatment arms showed a 3-year failure-free survival (FFS) rate of 72% in the standard arm, 86% in the ibrutinib without ASCT arm, and 88% in the ibrutinib with ASCT arm, Dreyling states. Although overall survival (OS) data are not fully mature, the 3-year OS rates showed that patients receiving the ibrutinib induction/maintenance experience improved outcomes compared to patients receiving standard ASCT alone.

Moreover, investigators originally postulated that ASCT would retain its status as the current standard of care if it demonstrated superiority over ibrutinib, Dreyling continues. However, ibrutinib-containing arms demonstrated improved FFS, clinically meaningful benefit, and OS benefit regardless of whether ASCT was administered, he says. 

Although no verdict on the role of ASCT has been reached, the ibrutinib without ASCT regimen was also associated with decreased toxicity, implying that ASCT may no longer be considered a standard treatment component for this patient population.

Martin Dreyling, MD, discusses key efficacy results from the phase 3 TRIANGLE study in mantle cell lymphoma.

Dr. Dreyling on Key Efficacy Results From the TRIANGLE Study in MCL

Martin Dreyling, MD, professor of medicine, University of Munich Hospital in Grosshadern, discusses primary results of the pivotal CHRONOS-1 study, which looked at copanlisib in patients with relapsed or refractory indolent B-cell lymphoma, during the AACR Annual Meeting.

Although there are treatments options currently available for these patients, all of the 142 patients included in the study had already undergone at least 2 prior lines of therapy, with the majority of the patients being refractory to the previous approaches.

Surprisingly, these patients still responded to the PI3K inhibitor copanlisib, Dreyling says. In fact, there was almost a 60% response rate demonstrated in the study. In marginal zone lymphoma, the response rate was almost 70%, and the duration of the response was 22 months, Dreyling explains.

With regard to toxicity, Dreyling adds there was no major colitis observed, and elevated liver enzymes have rarely been observed.

Martin Dreyling, MD, associate professor, University of Munich, discusses primary results of the pivotal CHRONOS-1 study, which looked at copanlisib in patients with relapsed or refractory indolent B-cell lymphoma, during the AACR Annual Meeting.