Patients with no detectable cancer after initial therapy for mantle cell lymphoma (MCL) did not experience any survival benefit from undergoing a stem cell transplant compared with maintenance therapy alone.
This is a conclusion based on study findings presented during the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7 – 10, 2024 in San Diego, CA, and online.
The phase 3 study called ECOG-ACRIN EA4151 (NCT03267433) was designed to investigate rituximab (Rituxan®; Genentech/Biogen) after stem cell transplant and to see how well it works compared with rituximab alone in treating patients with minimal residual disease-negative mantle cell lymphoma in first complete remission.
Based on the results of an interim analysis conducted when the study had followed patients for a median of 2.7 years, the study was stopped early.
No stem-cell transplant
According to researchers, the findings suggest that patients who test negative for minimal residual disease (MRD) with an ultra-high sensitivity blood test do not need to undergo a stem cell transplant or the high-dose chemotherapy regimen used to prepare for a transplant.
“I think these results will make physicians comfortable omitting the transplant in patients who are MRD-negative; in the current treatment landscape for MCL, we can achieve good outcomes for these patients without the high-dose chemotherapy and transplant,” said the study’s lead author, Timothy S. Fenske, MD, professor of medicine at Medical College of Wisconsin in Milwaukee.
“For patients who remain MRD-positive following induction, we would consider offering transplant,” Fenske added.
Mantle cell lymphoma
Mantel cell lymphoma or MCL, is a rare,* aggressive form of B cell non-Hodgkin lymphoma (NHL), a type of blood cancer, that develops in the ‘mantle zone‘ or outer ring of small lymphocytes surrounding the center of a lymphatic nodule.
Although the exact cause of MCL remains unknown, the development of the disease includes an abnormal buildup of cancerous B-lymphocytes in the lymph nodes. This buildup occurs when the lymphocytes divide too often, which is a result of disordered cell cycle regulation.
In most cases, MCL is diagnosed at a later stage of the disease and involves the gastrointestinal tract and bone marrow. Studies have shown that the overproduction of cyclin D1,** a protein that regulates the cell cycle and is a tumor marker that can be used to help diagnose and treat cancer, is found in the lymphoma cells in more than 90% of patients diagnosed with MCL. Identification of excess cyclin D1 from a biopsy is considered a very sensitive tool for diagnosing MCL.
Despite any therapeutic advances, MCL, which is more common in older adults and has, historically, a poor prognosis, remains a largely incurable neoplasm.
However, the disease can be managed, which can be challenging due to the heterogeneity of the disease course, with both indolent and aggressive subtypes. [2] Although treatments for patients with relapsed/refractory (R/R) disease are limited in number and response durability, current standard-of-care treatment options range from conventional chemoimmunotherapy and stem cell transplantation to targeted therapies against BTK (covalent and noncovalent), Bcl2, ROR1, cellular therapy such as anti-CD19 chimeric antigen receptor therapy (CAR-T), and most recently bispecific antibodies against CD19 and CD20. [3][4]
However, if the disease develops slowly and doesn’t cause symptoms, watchful waiting may be an option.[4]
Changing practice
After initial chemotherapy, doctors often recommend that patients undergo high-dose chemotherapy followed by an autologous stem cell transplant (using healthy stem cells collected from the patient’s own bone marrow) to help reduce the level of residual lymphoma further. However, this practice is based on studies conducted before today’s newer, more effective chemotherapy, immune therapy, and targeted therapies were available. In addition to the ECOG-ACRIN EA4151 study, one other recent randomized clinical trial assessed whether a stem cell transplant is still necessary in light of the improved efficacy of today’s induction and maintenance chemotherapy regimens.
“A stem cell transplant can be a hard process for patients to get through,” Fenske said, noting that the side effects can last for months, and the potential complications of the procedure can be especially risky for older people.
“If we can avoid that piece and still have similar outcomes, that would be a nice step forward,” he further noted.
The trial enrolled 650 patients between 2017-2024 who were in their first remission after initial treatment for MCL. Participants had a median age of 60 years, 79% were male, and 92% were white. Researchers assessed each patient’s remission status using a PET/CT scan, a bone marrow biopsy, and a highly sensitive blood test. They then divided participants into three groups based on the test results: MRD-negative (no evidence of cancer), MRD-positive (evidence of cancer in one or more cells per million), or MRD-indeterminate (testing incomplete or evidence of cancer in greater than zero but less than one cell per million).
The 516 patients who tested MRD-negative were randomly assigned to receive either a stem cell transplant and three years of maintenance rituximab or three years of maintenance rituximab alone. The rest of the patients (MRD-positive and MRD-indeterminate) were assigned to receive a stem cell transplant and three years of maintenance rituximab.
At the time of the most recent interim analysis, researchers determined that there was no evidence that a difference would emerge between the randomized arms of the MRD-negative group. With a median follow-up of 2.7 years, the overall survival rate was 82.1% among those assigned to receive a stem cell transplant and 82.7% among those assigned to maintenance therapy alone. The rate of survival without disease progression was 76.6% among those assigned to receive a stem cell transplant and 77.4% among those assigned to maintenance therapy alone.
About one-quarter of participants who tested MRD-negative and were randomized to receive a stem cell transplant refused to undergo the transplant. The researchers conducted a separate analysis to compare outcomes among participants who received their assigned treatment regimen, and found the survival rates were still similar enough to conclude there was no difference between groups.
The researchers also found no differences in outcomes among the randomized groups based on patients’ MIPI-c levels (a prognostic index for MCL) or the intensity of the induction therapy patients had undergone to achieve their first remission. Overall and progression-free survival rates were also similar among participants who were MRD-positive or MRD-indeterminate and assigned to receive a stem cell transplant.
Based on the evidence from this trial, researchers said that patients who test MRD-negative can safely avoid a stem cell transplant – and the associated side effects and risks – since they are likely to see no additional survival benefit from undergoing the procedure. One difference between ECOG-ACRIN EA4151 study and other trials is that there were no restrictions on the induction therapy regimen used to achieve the first remission. Researchers noted that this makes the results generalizable across different settings since it reflects the real-world variability in regimens used by different doctors and hospitals across the U.S.
Although the study stopped enrolling new patients, researchers will continue to follow participants for several more years to assess longer-term survival. They also plan to study molecular markers to determine whether different subgroups of patients may receive more benefit from a stem cell transplant.
Funding
This study was funded by the U.S. National Institutes of Health’s National Cancer Institute (NCI) and designed and implemented by ECOG-ACRIN Cancer Research Group. Cancer centers and community hospitals participated in the trial through two large NCI research programs: the National Clinical Trials Network (NCTN) and the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN).
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Note: * the disease accounts for approximately 5-10% of all non-Hodgkin lymphomas (NHL).
** Cyclin D1 is one of a family of 3 unlinked D type cyclin genes, CCND1, 2, 3.
Clinical trials
Rituximab With or Without Stem Cell Transplant in Treating Patients With Minimal Residual Disease-Negative Mantle Cell Lymphoma in First Complete Remission – ClinicalTrials.gov ID NCT03267433
Highlights of Prescribing Information
Rituximab (Rituxan®; Genentech/Biogen)[Prescribing Information]
Reference
[1] Fenske TS, Wang XV, Brian Till BG, Blum KA, Lunning M, Lazarus HM, Fishkin PAS, Shields LK, et al. Lack of Benefit of Autologous Hematopoietic Cell Transplantation (auto-HCT) in Mantle Cell Lymphoma (MCL) Patients (pts) in First Complete Remission (CR) with Undetectable Minimal Residual Disease (uMRD): Initial Report from the ECOG-ACRIN EA4151 Phase 3 Randomized Trial. LBA-6, presented on Tuesday, December 10, 2024, during a late-breaking abstracts session at the 66th American Society of Hematology Annual Meeting and Exposition.
[2] Wilson MR, Barrett A, Cheah CY, Eyre TA. How I manage mantle cell lymphoma: indolent versus aggressive disease. Br J Haematol. 2023 Apr;201(2):185-198. doi: 10.1111/bjh.18697. Epub 2023 Feb 20. PMID: 36807902.
[3] Ryan CE, Armand P, LaCasce AS. Frontline Treatment of Mantle Cell Lymphoma. Blood. 2024 Mar 18:blood.2023022352. doi: 10.1182/blood.2023022352. Epub ahead of print. PMID: 38498174.
[4] Jain P, Wang ML. Mantle cell lymphoma in 2022-A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments. Am J Hematol. 2022 May;97(5):638-656. doi: 10.1002/ajh.26523. PMID: 35266562.
Featured image: Attendees during General Views at the American Society of Hematology 64th Annual Meeting, December 10, 2022. Photo courtesy: 2022 – 2024 © ASH/Matt Herp. used with permission.
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