Thomas M. Habermann, MD, consultant, Division of Hematology, Department of Internal Medicine, professor of medicine, Mayo Clinic, member, the Lymphoma Research Foundation’s Scientific Advisory Board, discusses ongoing clinical trials in mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL). 

The formal publication of findings from the phase 3 TRIANGLE trial (NCT02858258) are anticipated, and data from the study presented at the 2022 ASH Annual Meeting could potentially be practice changing, Habermann says. The randomized trial evaluated ibrutinib (Imbruvica) plus induction chemotherapy with or without autologous stem cell transplant (ASCT) vs induction chemotherapy plus ASCT alone in younger patients with MCL. Findings showed that the 3-year failure-free survival (FFS) rate was 72% with standard induction and ASCT compared with 88% with ibrutinib added to induction, ASCT, and 2 years of ibrutinib maintenance (HR, 0.52; 

 = .0008). The 3-year FFS rate was 72% for chemoimmunotherapy/ASCT compared with 86% for ibrutinib alone (HR, 1.77; 

Based on these outcomes, ibrutinib may replace ASCT as the new standard of care for this patient population, Habermann says. However, the additional results from this study are still anticipated, which will allow for further interpretation. 

In addition to the TRIANGLE study, across the fields of MCL and MZL, the results of various phase 2 and phase 3 trials are pending, Habermann says. For example, a phase 3 trial (NCT04002297) is examining zanubrutinib (Brukinsa) plus rituximab (Rituxan) vs bendamustine (Bendeka) plus rituximab in previously untreated patients with MCL. The study is ongoing and data have not yet been reported. Additionally, data from a phase 3 trial (NCT02972840) evaluating bendamustine and rituximab with or without acalabrutinib (Calquence) in patients with treatment-naïve MCL are also pending, Habermann says, indicating that this is a different approach than what has previously been studied.

Finally, a multicenter, randomized, double-blind, placebo-controlled phase 3 trial (NCT04212013) is investigating the use of ibrutinib in combination with rituximab vs ibrutinib plus placebo in patients with treatment-naïve MZL, Habermann concludes.

Videos

Thomas M. Habermann, MD, discusses ongoing clinical trials in mantle cell lymphoma and marginal zone lymphoma.


Dr Habermann on Ongoing Trials in MCL and MZL

Thomas M. Habermann, MD, consultant, Division of Hematology, Department of Internal Medicine, professor of medicine, Mayo Clinic, member, the Lymphoma Research Foundation’s Scientific Advisory Board, discusses the data that led to the decision to withdraw the indication for ibrutinib (Imbruvica) for the treatment of patients with mantle cell lymphoma (MCL).

AbbVie announced the intention to voluntarily withdraw indications for ibrutinib

 for the treatment of patients with MCL who have previously received at least 1 therapy and in those with marginal zone lymphoma (MZL) who require systemic treatment and have received at least 1 prior anti–CD20-based therapy. This decision was based on data from the phase 3 SHINE trial (NCT01776840) for MCL and the phase 3 SELENE trial (NCT01974440) for MZL.

Ibrutinib had received accelerated approval for the treatment of patients with MCL based on the overall response rate (ORR) observed in the phase 2 Study 1104 trial (NCT01236391). In the single-arm study, patients were treated with 560 mg of oral ibrutinib daily, and in 111 patients, the BTK inhibitor elicited an ORR of 65.8% (95% CI, 56.2%-74.5%), including a complete response rate of 17.1%.

SHINE served as a confirmatory trial for the accelerated approval for the MCL indication. The study was conducted the frontline setting for patients with MCL, who were randomly assigned to receive ibrutinib or placebo in combination with bendamustine and rituximab (Rituxan).

Data from SHINE showed that at a median follow-up of 84.7 months (range, 0.1-97.5), the median progression-free survival (PFS) was 80.6 months (95% CI, 61.9–not evaluable) for the ibrutinib arm vs 52.9 months (95% CI, 43.7-71.0) for the placebo arm, meeting the primary end point of the trial (stratified HR, 0.75; 95% CI, 0.59-0.96; 

 = .01). Although the PFS benefit was observed across the majority of prespecified subgroups for the ibrutinib regimen, those with a simplified MIPI score of high risk and those whose tumors harbored 

 mutations did not derive a clear benefit.

However, the ORR was 89.7% in the ibrutinib arm and 88.5% in the placebo arm. Overall survival (OS) was comparable between the 2 arms (HR, 1.07; 95% CI, 0.81-1.40). Additionally, the rates of grade 3/4 adverse effects were 81.5% in the ibrutinib arm vs 77.3% in the control arm.

Thomas M. Habermann, MD, discusses the data that led to the decision to withdraw the indication for ibrutinib for the treatment of patients with mantle cell lymphoma.

Dr Habermann on Data Leading to the Withdrawal of Ibrutinib in MCL

Thomas M. Habermann, MD, consultant, Division of Hematology, Department of Internal Medicine, professor of medicine, Mayo Clinic, member, the Lymphoma Research Foundation’s Scientific Advisory Board, discusses the withdrawal of United States indications for ibrutinib (Imbruvica) in patients with mantle cell lymphoma (MCL) who have previously received at least 1 therapy and in those with marginal zone lymphoma (MZL) who require systemic treatment and have received at least 1 prior anti–CD20-based therapy.

AbbVie announced its intention to voluntarily withdraw ibrutinib in these 2 indications

 in the United States. No other indications for ibrutinib were affected. The decision was made following results of the phase 3 SHINE trial (NCT01776840) in patients with MCL and phase 3 SELENE (NCT01974440) trial in patients with indolent non-Hodgkin lymphoma, including follicular lymphoma and MZL.

Both SHINE and SELENE served as confirmatory trials following accelerated FDA approvals for ibrutinib for these 2 indications. Findings from SHINE published in 

 showed that although the study met its primary end point of progression-free survival (PFS), the combination of ibrutinib and chemoimmunotherapy was associated with more toxicity vs chemoimmunotherapy alone, Habermann begins. Although full data from SELENE have not yet been published, the study failed to meet it primary end point of PFS, Habermann notes.

SHINE included patients with previously untreated MCL, and SELENE enrolled previously treated patients with follicular lymphoma patients and MZL, Habermann adds. SHINE evaluated ibrutinib in combination with bendamustine (Treanda) and rituximab (Rituxan) vs bendamustine and rituximab alone. SELENE examined ibrutinib in combination with bendamustine and rituximab, or in combination with R-CHOP. Both trials were placebo controlled and both had PFS as the primary end point.

Thomas M. Habermann, MD, discusses the withdrawal of United States indications for ibrutinib in patients with mantle cell lymphoma who have previously received at least 1 therapy and in those with marginal zone lymphoma who require systemic treatment and have received at least 1 prior anti–CD20-based therapy.


Dr Habermann on the Withdrawal of U.S. Indications for Ibrutinib in MCL and MZL

Thomas M. Habermann, MD, consultant, Division of Hematology, Department of Internal Medicine, professor of medicine, Mayo Clinic, member, the Lymphoma Research Foundation’s Scientific Advisory Board, discusses the evolving treatment landscape of mantle cell lymphoma (MCL).

Although ibrutinib (Imbruvica) has been well established as a treatment for patients with relapsed/refractory MCL, the emergence of other BTK inhibitors have provided other options for these patients, Habermann explains. Ongoing randomized clinical trials are evaluating ibrutinib and the other 3 approved BTK inhibitors: acalabrutinib (Calquence), zanubrutinib (Brukinsa), and pirtobrutinib (Jaypirca). In January 2023, 

the FDA approved pirtobrutinib for the treatment of adult patients with relapsed or refractory MCL

 following at least 2 lines of systemic therapy, including a BTK inhibitor. The ongoing phase 3 BRUIN-MCL-321 trial (NCT04662255) is evaluating pirtobrutinib vs the other 3 approved BTK inhibitors in patients with MCL who received at least 1 prior line of therapy and have not been treated with a BTK inhibitor.

Additionally, CAR T-cell therapy has earned a role for patients with MCL who have had multiple relapses, Habermann expands. 

The FDA approved brexucabtagene autoleucel

 (Tecartus; formerly KTE-X19) as a treatment for adult patients with relapsed/refractory MCL in July 2020.

Moreover, the phase 3 TRIANGLE study (NCT02858258) showed that ibrutinib plus standard chemoimmunotherapy followed by autologous stem cell transplant (ASCT) and 2 years of maintenance ibrutinib significantly improved outcomes vs standard chemoimmunotherapy induction and ASCT alone for younger patients with MCL.

Thomas M. Habermann, MD, discusses the evolving treatment landscape of mantle cell lymphoma.

Thomas M. Habermann, MD

Articles

Dr Habermann on Ongoing Trials in MCL and MZL

Dr Habermann on Data Leading to the Withdrawal of Ibrutinib in MCL

Dr Habermann on the Withdrawal of U.S. Indications for Ibrutinib in MCL and MZL

Dr Habermann on the Evolving Treatment Landscape of Mantle Cell Lymphoma