Researchers have revealed that high-dose chemotherapy followed by autologous stem cell transplantation may not benefit patients with mantle cell lymphoma (MCL) who are in remission following initial treatment, according to new findings presented by Fenske et al at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract LBA-6).
Background
MCL is an incurable hematologic malignancy that tends to occur more frequently in male patients and older patients with a median age of 65 years. In about 90% of cases, MCL is fast growing and requires immediate treatment upon diagnosis. Historically, the disease was associated with poor outcomes; however, outcomes have recently improved as more effective and targeted therapies have become available. Currently, the first remission can be 8 to 10 years or longer.
Several standard front-line and maintenance treatment options exist—including intensive chemotherapy, immunotherapy, targeted drugs, and Bruton's tyrosine kinase inhibitors. The targeted immunotherapy drug rituximab is one of the treatment options for MCL.
For many years, it has been common practice to offer patients under age 70 years an autologous stem cell transplantation if they are deemed physically fit enough to withstand the difficult procedure, which involves high-dose chemotherapy followed by reinfusion of the patient’s own blood stem cells.
“EA4151 is the first randomized trial to study [autologous stem cell transplantation] for patients [with MCL] with undetectable MRD in first remission, within an era of highly effective induction and maintenance regimens. The benefit of [autologous stem cell transplantation] in this current era has been debated heavily, because the data suggesting benefit of [the procedure] all came from the context of older trials and treatments,” explained lead study author Timothy S. Fenske, MD, Professor of Medicine at the Medical College of Wisconsin.
Study Methods and Results
In the phase III EA4151 study, the researchers assigned 650 patients to undergo positron-emission tomography/computed tomography (PET/CT) imaging, bone marrow biopsies, and blood draws between August 2017 and July 2024. Blood was tested for the presence of any remaining cancer cells using a highly sensitive, commercial measurable residual disease (MRD) assay cleared by the U.S. Food and Drug Administration. The test was capable of detecting traces of residual lymphoma below the level of that which standard imaging and blood testing can detect.
Patients with MCL who were in first complete remission following induction therapy were eligible to join the trial. Cancer centers and community hospitals participated in the trial through two large National Cancer Institute (NCI) research programs: the National Clinical Trials Network and the Blood and Marrow Transplant Clinical Trials Network.
The researchers initially hypothesized that the patients who were already in deep remission with negative PET/CT scans, bone marrow biopsies, and MRD testing would be less likely to benefit from autologous stem cell transplantation. These patients may be able to safely avoid the risks of the transplant procedure.
The researchers found that 79% (n = 516) of the patients who participated in the trial had complete remission with undetectable MRD following induction therapy. These patients were randomly assigned to receive either an autologous stem cell transplant followed by 3 years of rituximab (arm A, n = 257) or 3 years of rituximab alone (arm B, n = 259). The primary endpoint of the study was to compare overall survival between both groups.
After a median follow-up of 2.7 years, the researchers discovered that the 3-year overall survival rates were 82.1% in the patients who received autologous stem cell transplantation plus rituximab vs 82.7% in the patients who received rituximab alone.
The remaining patients in the trial experienced either MRD-positive complete remission or partial response (arm C, n = 49) or MRD-indeterminate or partial response with undetectable MRD (arm D, n = 85). They received autologous stem cell transplantation plus 3 years of rituximab. The 3-year overall survival was 81.9% in arm C and 85.1% in arm D.
Progression-free survival was a secondary endpoint of the study. The 3-year progression-free survival rate was also similar across all four treatment groups: 76.6%, 77.4%, 76.9%, and 73.4% in arms A through D, respectively.
Immediately following the interim analysis, the ECOG-ACRIN Data Safety and Monitoring Committee halted enrollment for the trial early after a planned interim analysis showed no statistically significant differences in overall survival between the study groups. The researchers subsequently stopped patient accrual, informed the trial participants, and made the results public. Their related futility analysis showed that the outcome was likely to be similar when the study reached the planned analysis with total enrollment and complete information.
Conclusions
“In this interim analysis, patients [with MCL] in first complete remission with undetectable [MRD] did not benefit from consolidative [autologous stem cell transplantation],” emphasized Dr. Fenske. “Patients who remain MRD-positive after induction may benefit from [autologous stem cell transplantation]. Longer follow-up will be important to confirm these findings,” he concluded.
Disclosure: The research in this study was funded by the NCI of the National Institutes of Health as well as designed and implemented by the ECOG-ACRIN Cancer Research Group. For full disclosures of the study authors, visit ash.confex.com.
