May-June 2019, Volume 16, Issue 3
Can We Use MRD Status to Personalize Therapy in Mantle Cell Lymphoma?
Published on: April 11, 2019
Study Title: A Randomized Phase III Trial of Consolidation with Autologous Hematopoietic Cell Transplantation Followed by Maintenance Rituximab vs. Maintenance Rituximab Alone for Patients with Mantle Cell Lymphoma in Minimal Residual Disease-Negative First Complete Remission (ECOG-ACRIN 4151)
ISRCTN Number: NCT03267433
Sponsor: ECOG-ACRIN Cancer Research Group; National Cancer Institute (NCI)
Accrual Goal: 412 patients randomized to arms A and B (206 patients to each arm)
Participating Centers: All ECOG-ACRIN sites (lead organization) and Cancer Trials Support Unit sites (including Alliance and Southwest Oncology Group). The study also is endorsed by the Blood and Marrow Transplant Clinical Trials Network. The study is open at both academic centers as well as at some larger community oncology practices.
Study Design: This trial is enrolling adult patients with mantle cell lymphoma (MCL) aged 18 to 70 years, who are considered candidates for autologous hematopoietic cell transplantation (auto-HCT). Patients are enrolled at any time during first-line therapy. The study will allow any induction regimen (per their treating physician’s preference), and patients have the option to receive their induction regimen by their community oncologist. After completion of induction therapy, patients will undergo restaging with a PET/CT scan, bone marrow biopsy, and minimal residual disease analysis (MRD) using an immunoglobulin high-throughput sequencing (next-generation sequencing) circulating tumor DNA (ctDNA) assay. The MRD assay has a high sensitivity, being able to detect approximately one in 1,000,000 ctDNA sequences in the peripheral blood. Patients who are in an MRD-negative complete remission (CR) are then randomized to either auto-HCT followed by three years of maintenance rituximab (arm A) or three years of maintenance rituximab with deferral of auto-HCT (arm B). Patients who remain MRD positive or who are in a partial remission will proceed to auto-HCT followed by three years of maintenance rituximab (arm C). Patients with “indeterminate” MRD status will proceed to auto-HCT followed by three years of maintenance rituximab (arm D).
The primary objective of the study is to compare six-year overall survival (OS) between auto-HCT followed by maintenance rituximab (arm A) versus maintenance rituximab alone (a rm B) in patients in MRD-negative first CR. The secondary objectives include four-year progression-free survival (PFS) for MRD-negative patients, as well as PFS and OS for MRD-positive patients (or patients in partial remission) who undergo auto-HCT followed by maintenance rituximab, and MRD status at day 100 in MRD-positive patients prior to auto-HCT.
Rationale: The OS benefit of auto-HCT in first-line therapy for MCL following modern induction regimens is unproven. The only prospective randomized trial comparing transplantation to nontransplantation, published in 2005 prior to the advent of modern induction regimens, did not show a survival benefit.1 The average patient with MCL is in the 65-to-70–year age range and frequently have significant comorbidities, increasing the risk of serious toxicity with auto-HCT. Additionally, MCL is a disease with considerable biological and clinical heterogeneity, making patients with MCL an ideal population for a risk-adapted approach.2 Several published studies have shown that patients who achieve MRD negativity following first-line therapy have superior outcomes.3-6 The study hypothesis is that MCL patients who achieve an MRD-negative first CR benefit less from auto-HCT.
Comment: This is a bold and important study, randomizing young patients with MCL in first CR (must be MRD negative) to auto-HCT or no auto-HCT. All patients received three years of maintenance rituximab as it has shown survival benefit in patients receiving transplant as well as nontransplant-based first-line therapy.7,8 Historically in MCL, practice patterns are developed based upon small and imperfect datasets combined with physician preferences and biases. This study represents the largest North American effort to date in MCL and will generate helpful data for physicians and patients. The study chairs have intentionally designed an accrual-friendly study. Acknowledging that many different regimens are used in the treatment of MCL, the study allows any induction regimen and various auto-HCT conditioning regimens. Patients may be enrolled at their community oncology site or at the site where they undergo evaluation for transplantation. Maintenance rituximab can be received at the patient’s community oncology site as well.
Lenz G, Dreyling M, Hoster E, et al. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005;23:1984-1992.
Cheah CY, Seymour JF, Wang ML. Mantle cell lymphoma. J Clin Oncol. 2016;34:1256-1269.
Pott C, Hoster E, Delfau-Larue MH, et al. Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study. Blood. 2010;115:3215-3223.
Kolstad A, Laurell A, Jerkeman M, et al. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood. 2014;123:2953-2959.
Gressin R, Daguindau N, Tempescul A, et al. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first-line treatment of older patients with mantle cell lymphoma. Haematologica. 2019;104:138-146.
Cowan AJ, Stevenson PA, Cassaday RD, et al. Pretransplantation minimal residual disease predicts survival in patients with mantle cell lymphoma undergoing autologous stem cell transplantation in complete remission. Biol Blood Marrow Transplant. 2016;22:380-385.
Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367:520-531.
Le Gouill S, Thieblemont C, Oberic L, et al. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377:1250-1260.
Conflict of Interests
Dr. Kahl has no relevant conflicts of interest. Dr. Fenske served as a consultant and speaker for Genentech (makers of rituximab) and Adaptive Biotechnologies (owners of the clonoSEQ minimal residual disease assay).
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