Autologous stem cell transplantation (ASCT) does not improve survival outcomes for patients with mantle cell lymphoma who achieve a deep first complete remission with undetectable measurable residual disease (MRD) after induction therapy, according to data presented during the 2024 American Society of Hematology (ASH) Annual Meeting & Exhibition.¹

Initial results of the ECOG-ACRIN EA4151 trial showed that ASCT provided no significant benefit in overall survival or progression-free survival for these patients, regardless of treatment assigned or treatment received. Exploratory findings, however, suggested that patients who remain MRD-positive after induction may benefit from ASCT if their MRD status converts to undetectable posttransplant. Authors of the study emphasized that these findings highlight a shift in the role of ASCT in the context of increasingly effective induction and maintenance regimens for mantle cell lymphoma.

“This study underscores the importance of MRD testing in tailoring treatment decisions for mantle cell lymphoma, particularly in an era of highly effective induction therapies,” said lead study author Timothy S. Fenske, MD, MS, Professor of Medicine, formerly at the Medical College of Wisconsin, Milwaukee, during a virtual press briefing. (Dr. Fenske is currently Medical Director of Immune Effector Cell Therapy with the Sarah Cannon Transplant & Cellular Therapy Program at Methodist Hospital, San Antonio.) As Dr. Fenske explained, the use of ASCT as consolidation therapy for mantle cell lymphoma in first remission has been standard practice for years, but its role has been questioned considering more effective induction and maintenance regimens.

“There has been ongoing controversy about whether ASCT still provides meaningful survival benefits in the modern treatment landscape.”

— Timothy S. Fenske, MD, MS

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“There has been ongoing controversy about whether ASCT still provides meaningful survival benefits in the modern treatment landscape,” said Dr. Fenske. “The ECOG-ACRIN EA4151 trial was designed to address that question, focusing on patients in first complete remission with the deepest levels of MRD negativity.”

The trial allowed any rituximab-containing induction regimen, including those with Bruton’s tyrosine kinase (BTK) inhibitors, to reflect the variability in mantle cell lymphoma treatment practices across the United States.

Study Design

The ECOG-ACRIN EA4151 trial enrolled patients aged 18 to 70 with mantle cell lymphoma who achieved first complete remission after induction therapy. All patients underwent MRD assessment using a highly sensitive sequencing-based assay capable of detecting 1 lymphoma cell in 1 million (ClonoSEQ).

Patients with undetectable MRD were randomly assigned one to one to arm A (ASCT followed by 3 years of rituximab maintenance) or arm B (rituximab maintenance alone, without ASCT). Patients with MRD-positive disease (arm C) or indeterminate MRD (arm D) received ASCT followed by rituximab maintenance.

Randomization was stratified by the Mantle Cell International Prognostic Index (MIPI) score and the intensity of induction therapy, with intensive regimens including high-dose cytarabine. More than 250 patients were enrolled in each of arms A and B. Baseline characteristics were well balanced, including age, sex, MIPI score, and induction intensity.

A total of 7% to 8% of patients received BTK inhibitors during induction. Approximately 25% of patients randomly assigned to ASCT declined the procedure, opting instead for rituximab maintenance alone, reflecting concerns about the potential toxicity of transplantation, said Dr. Fenske.

No Significant Difference in Survival Outcomes

The primary endpoint of overall survival showed no significant difference between arms A and B. As Dr. Fenske reported, this was consistent across the intent-to-treat analysis and the as-treated analysis, which accounted for patients who declined their assigned treatment. Similarly, progression-free survival outcomes were comparable between the two arms, with no significant differences observed regardless of treatment assignment or adherence.

“Based on the futility analysis our statistical team performed, even with longer follow-up, it is highly unlikely that ASCT will show a meaningful survival benefit for patients with undetectable MRD in first remission,” Dr. Fenske observed.

In arm C, which included MRD-positive patients after induction, posttransplant MRD conversion was associated with improved outcomes. Patients whose MRD status converted to undetectable posttransplant had significantly better survival and progression-free survival than did those whose MRD remained positive. However, Dr. Fenske noted that these latter findings are exploratory and require further validation.

Other than COVID-19 deaths, affecting approximately 5% of patients (regardless of receiving ASCT), adverse events were consistent with previous studies of rituximab maintenance and ASCT, with no unexpected toxicities observed, Dr. Fenske reported.

Clinical Implications

According to Dr. Fenske, these results provide compelling evidence that ASCT may no longer be necessary for patients with mantle cell lymphoma in first complete remission who have undetectable MRD. For patients with MRD-positive disease after induction, on the other hand, ASCT remains a potentially beneficial option, he said, particularly for those who achieve MRD conversion posttransplant.

“This trial demonstrates the critical role of MRD testing in guiding treatment decisions,” Dr. Fenske concluded. “While longer follow-up is needed to confirm these findings, our initial results suggest that consolidation with ASCT may not be necessary for all patients in first remission, particularly those with undetectable MRD.”

Ongoing analysis will focus on long-term outcomes and refining the role of ASCT in the context of new therapeutic advancements for mantle cell lymphoma. 

DISCLOSURE: Dr. Fenske has served as a consultant for, been a member of a speakers bureau for, and/or received honoraria from AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, Bayer, BeiGene, Kite, Seagen, Lilly, Ipsen, and Ono Pharma.

REFERENCE

1. Fenske TS, Wang XV, Till BG, et al: Lack of benefit of autologous hematopoietic cell transplantation in mantle cell lymphoma patients in first complete remission with undetectable minimal residual disease: Initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. 2024 ASH Annual Meeting & Exposition. Abstract LBA-6. Presented December 9, 2024.

EXPERT POINT OF VIEW

Jeremy S. Abramson, MD, MMSc, Director of the Lymphoma Program at the Massachusetts General Hospital Cancer Center, and Associate Professor of Medicine at Harvard Medical School, Boston, underscored the paradigm shift in the role of autologous stem cell transplantation for patients with mantle cell lymphoma, as demonstrated by the ECOG-ACRIN EA4151 trial.

Jeremy S. Abramson, MD, MMSc

“Interim results from the EA4151 study, along with updated results from the TRIANGLE study¹ reported at the same meeting, confirm that we should stop performing autologous stem cell transplants for the vast majority of patients with mantle cell lymphoma,” Dr. Abramson told The ASCO Post. “While autologous stem cell transplant was shown to offer a modest benefit in a prior era of mantle cell lymphoma therapy, numerous advances in treatment since that time have rendered the transplant unnecessary in the modern era.” He added: “This is a huge advance for patients, as it avoids significant toxicities associated with high-dose chemotherapy.”

Dr. Abramson also addressed the broader implications of these findings for treatment strategy, particularly the use of measurable residual disease (MRD) testing. “The EA4151 and TRIANGLE¹ studies offer us two different approaches to avoid autologous stem cell transplant in the initial management of mantle cell lymphoma,” Dr. Abramson explained. “The EA4151 approach is MRD-driven, requiring testing for MRD and omitting the transplant in the large majority of patients who are MRD-undetectable at the end of treatment.”

He continued: “The TRIANGLE approach, however, does not require MRD testing. In that approach, the BTK [Bruton’s tyrosine kinase] inhibitor ibrutinib is included with induction and maintenance therapy for all patients, thus obviating the need for stem cell transplant consolidation.”

Although both strategies are viable, Dr. Abramson expressed a preference for the TRIANGLE approach in clinical practice. “Given the clear improvement in the TRIANGLE study for inclusion of the BTK inhibitor with chemoimmunotherapy and maintenance, I am favoring that approach in my patients and am not routinely checking for MRD,” he concluded. “Future research should assess the value of MRD in guiding treatment decisions for patients treated with a BTK inhibitor–based regimen upfront.” 

DISCLOSURE: Dr. Abramson has served as a consultant for AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, Celgene, Cellectar, Foresight Diagnostics, Genentech, Gilead Sciences, Interius Bio Therapeutics, Lilly, Miltenyi Biotec, Novartis, Roche, and Seagen.

REFERENCE

1. Dreyling M, Doorduijn JK, Gine E, et al: Role of autologous stem cell transplantation in the context of ibrutinib-containing first-line treatment in younger patients with mantle cell lymphoma: Results from the randomized TRIANGLE trial by the European MCL Network. 2024 ASH Annual Meeting & Exhibition. Abstract 240. Presented December 7, 2024.